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Qu ic k Ta b le o f Co n t e n t s
Introduction to Pathophysiology x viii CHAPTER 27 Disorders of the Bladder and Lower Urinary
Tract 656
U N IT 1 C e ll a n d Tis s u e Fu n c t io n 1
CHAPTER 1 Cell Structure and Function 1 U N IT 8 G a s t ro in t e s t in a l a n d
He p a t o b ilia ry Fu n c t io n 675
CHAPTER 2 Cellular Responses to Stress, Injury, and
Aging 31 CHAPTER 28 Structure and Function of the Gastrointestinal
System 675
CHAPTER 3 In ammation, the In ammatory Response,
and Fever 49 CHAPTER 29 Disorders of Gastrointestinal Function 696
CHAPTER 4 Cell Proliferation and Tissue Regeneration CHAPTER 30 Disorders of Hepatobiliary and Exocrine
and Repair 71 Pancreas Function 724
CHAPTER 5 Genetic Control of Cell Function and U N IT 9 En d o c r in e S y s t e m 753
Inheritance 87
CHAPTER 31 Mechanisms of Endocrine Control 753
CHAPTER 6 Genetic and Congenital Disorders 106
CHAPTER 32 Disorders of Endocrine Control of Growth
CHAPTER 7 N eoplasia 129 and Metabolism 767
U N IT 2 In t e g r a t ive Bo d y Fu n c t io n s 15 9 CHAPTER 33 Diabetes Mellitus and the Metabolic
Syndrome 793
CHAPTER 8 Disorders of Fluid, Electrolyte, and AcidBase
Balance 159 U N IT 1 0 N e r vo u s S y s t e m 821
CHAPTER 9 Stress and Adaptation 206 CHAPTER 34 Organization and Control of N eural
CHAPTER 10 Disorders of N utritional Status 223 Function 821
CHAPTER 35 Somatosensory Function, Pain, and
U N IT 3 He m a t o p o ie t ic Fu n c t io n 241 Headache 854
CHAPTER 11 Disorders of White Blood Cells and Lymphoid CHAPTER 36 Disorders of N euromuscular Function 880
Tissues 241
CHAPTER 37 Disorders of Brain Function 916
CHAPTER 12 Disorders of Hemostasis 261
CHAPTER 38 Disorders of Special Sensory Function: Vision,
CHAPTER 13 Disorders of Red Blood Cells 277 Hearing, and Vestibular Function 955
U N IT 4 In f e c t io n a n d Im m u n it y 297 U N IT 11 G e n it o u r in a ry a n d Re p ro d u c t ive
CHAPTER 14 Mechanisms of Infectious Disease 297 Fu n c t io n 9 9 3
CHAPTER 15 Innate and Adaptive Immunity 318 CHAPTER 39 Disorders of the Male Genitourinary
CHAPTER 16 Disorders of the Immune Response 344 System 993
CHAPTER 40 Disorders of the Female Genitourinary
U N IT 5 C ir c u la t o ry Fu n c t io n 375 System 1017
CHAPTER 17 Control of Cardiovascular Function 375 CHAPTER 41 Sexually Transmitted Infections 1049
CHAPTER 18 Disorders of Blood Flow and Blood
Pressure 402 U N IT 1 2 M u s c u lo s k e le t a l Fu n c t io n 10 6 3
CHAPTER 19 Disorders of Cardiac Function 444 CHAPTER 42 Structure and Function of the Skeletal
System 1063
CHAPTER 20 Heart Failure and Circulatory Shock 486
CHAPTER 43 Disorders of the Skeletal System: Trauma,
U N IT 6 Re s p ir a t o ry Fu n c t io n 513 Infections, N eoplasms, and Childhood
Disorders 1078
CHAPTER 21 Control of Respiratory Function 513
CHAPTER 44 Disorders of the Skeletal System: Metabolic
CHAPTER 22 Respiratory Tract Infections, N eoplasms, and and Rheumatic Disorders 1111
Childhood Disorders 539
CHAPTER 23 Disorders of Ventilation and Gas U N IT 1 3 In t e g u m e n t a ry Fu n c t io n 11 4 1
Exchange 565 CHAPTER 45 Structure and Function of the
Integumentum 1141
U N IT 7 Kid n e y a n d U r in a ry Tr a c t
Fu n c t io n 5 9 9 CHAPTER 46 Disorders of Skin Integrity and
Function 1153
CHAPTER 24 Structure and Function of the Kidney 599
G lossary 1185
CHAPTER 25 Disorders of Renal Function 617
A ppendix A : L ab V alues 1197
CHAPTER 26 Acute Kidney Injury and Chronic Kidney
Disease 639 Index 1199

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Essentia ls of Pa thophysiology
Ed it io n 4

- V
9 . i r
CARO L M ATTSO N PO RTH , RN , M SN , PH D (Physiology), FAH A

i r 9 & ans s
Professor Emeritus, College of N ursing
h University of WisconsinM ilwaukee
ta r s i M ilwaukee, Wisconsin

p e
ip . Consultant
v Clinical Associate Professor Emeritus
University of WisconsinM ilwaukee
College of N ursing
M ilwaukee, Wisconsin

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Illustrator, 4th Edition: Wendy Beth Jackelow, M FA, CM I
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Co n t ri b u t o rs
Jacqueline M. Akert, RN C, MSN , Jason R. Faulhaber, MD Patricia McCowen Mehring, RN C,
WHN P-BC Division of Infectious Diseases, Carilion MSN , WHN P
N urse Practitioner, Women's H ealth Clinic N urse Practitioner
Aurora H ealth Care Assistant Program Director, Fellowship Women's H ealth
Waukesha, Wisconsin in Infectious Diseases, Carilion Clinic M ilwaukee, Wisconsin
(Chapters 40, 41 w ith Patricia Assistant Professor, Virginia Tech, (Chapter 40, 41 with Jacqueline M. Akert)
M cCow en M ehring) Carilion School of M edicine
Adjunct Professor, Department of Carrie J. Merkle, PhD, RN , FAAN
Aoy Tomita-Mitchell, PhD Biomedical Sciences, Jefferson Associate Professor
Associate Professor College of H ealth Sciences College of N ursing
Department of Surgery Roanoke, Virginia The University of Arizona
M edical College of Wisconsin (Chapters 15, 16) Tucson, Arizona
Childrens Research Institute (Chapters 1, 2, 3, 4, 7)
M ilwaukee, Wisconsin Anne M. Fink, RN , PhD
(Chapters 5, 6) Postdoctoral Research Associate Kathleen Mussatto, PhD, RN
University of IllinoisChicago N urse Scientist, H erma H eart Center
Diane Book, MD College of N ursing Childrens H ospital of Wisconsin
Associate Professor, N eurology Chicago, Illinois Assistant Clinical Professor of Surgery
Co-Director Stroke & N eurovascular (Chapters 19, 20 with Karen M. Vuckovic) M edical College of Wisconsin
Program M ilwaukee, Wisconsin
Froedtert H ospital & M edical College Susan A. Fontana, PhD, APRN -BC (Chapter 19, H eart D isease in Infants
of Wisconsin Associate Professor and Family N urse and Children)
M ilwaukee, Wisconsin Practitioner
(Chapter 37) University of WisconsinM ilwaukee Debra Bancroft Rizzo, RN , MSN ,
College of N ursing FN P-BC
Freddy W. Cao, MD, PhD M ilwaukee, Wisconsin N urse Practitioner
Clinical Associate Professor (Chapter 38) Division of Rheumatology
College of N ursing University of M ichigan
University of WisconsinM ilwaukee Kathleen E. Gunta, MSN , RN , OCN S-C Ann Arbor, M ichigan
M ilwaukee, Wisconsin Clinical N urse Specialist (Chapter 44)
(Chapters 18, 34) Aurora St. Luke's M edical Center
M ilwaukee, Wisconsin Jonathan Shoopman, MD
Paula Cox-N orth, PhD, ARN P (Chapter 43) Assistant Professor of Anesthesiology
H epatitis & Liver Clinic and Critical Care
H arborview M edical Center N athan A. Ledeboer, PhD, D(ABMM) M edical College of Wisconsin
Clinical Assistant Professor Associate Professor of Pathology M ilwaukee, Wisconsin
University of Washington School of M edical College of Wisconsin (Chapters 22, 23)
N ursing M ilwaukee, Wisconsin
Seattle, Washington (Chapter 14) Gladys Simandl, RN , PhD
(Chapters 29, 30) Professor
Kim Litwack, PhD, RN , FAAN , APN P Columbia College of N ursing
Herodotos Ellinas, MD, FAAP, FACP Associate Dean for Academic Affairs M ilwaukee, Wisconsin
Assistant Professor, Department of Family N urse Practitioner (Chapters 45, 46)
Anesthesiology Advanced Pain M anagement
M edAnesthesia and PGY-1 Program University of WisconsinM ilwaukee Karen M. Vuckovic, RN, PhD, ACNS-BC
Director M ilwaukee, Wisconsin Assistant Clinical Professor
M edical College of Wisconsin (Chapter 35) University of IllinoisChicago
M ilwaukee, Wisconsin College of N ursing
(Chapters 11, 12, 13) Glenn Mat n, MSc (Oxon), MB, ChB, Chicago, Illinois
FACE, FACP, FRCP (Chapters 19, 20 w ith A nne M . Fink )
M edical Director
International Diabetes Center Jill M. Winters, RN , PhD, FAHA
Clinical Professor of M edicine President and Dean
University of M innesota Columbia College of N ursing
M inneapolis, M innesota M ilwaukee, Wisconsin
(Chapters 10, 31, 32, 33, 39) (Chapter 9)

v ii

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Re v i e w e rs
Louise Boudreault, PhD Mini Jose, PhD, RN Cheryl N eudauer, PhD
Professor of Practical N ursing Assistant Professor Biology Faculty
Algonquin College University of Texas M edical Branch Center for Teaching and Learning
O ttawa, O ntario School of N ursing Co-Leader
Galveston, Texas M inneapolis Community and Technical
Freddy W. Cao, MD, PhD College
Clinical Associate Professor Michelle McDonald, MS M inneapolis, M innesota
College of N ursing Assistant Professor of Biology
University of WisconsinM ilwaukee Baptist College of H ealth Sciences Paige Wimberley, MSN , PhD(c)
M ilwaukee, Wisconsin M emphis, Tennessee Assistant Professor of N ursing
Arkansas State University
Lori Hendrickx, MSN , EdD Sandra McLeskey, PhD, RN Jonesboro, Arkansas
Professor of N ursing Professor
South Dakota State University University of M aryland School of
Brookings, South Dakota N ursing
Baltimore, M aryland
Lisa Hight, EdD
Associate Professor of Biology
Baptist College of H ealth Sciences
M emphis, Tennessee

v iii

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P re f a c e
As the 21st century unfolds, more information is avail- for easier learning. Clinical Features are illustrations
able to more people at a faster pace than ever before. that depict the clinical features of persons with selected
This ever-evolving ability to communicate has produced diseases. As with other types of illustrations in this edi-
phenomenal advances in the ability to understand and tion, they are designed to help the reader develop a
treat disease. Yet despite these advances, we are also visual memoryin this case, the memory of the entire
reminded that illness and disease continue to occur and spectrum of clinical manifestations that are associated
impact the physiologic, social, psychological, and eco- with a disease state.
nomic well-being of individuals, their families, the com- Review exercises appear at the end of each chapter
munity, and the world. and assist the reader in using the conceptual approach
As a nursephysiologist, my major emphasis with this to solving problems related to chapter content. The
edition, as in previous editions, is to relate normal body glossary de nes the specialized terms of pathophysiol-
functioning to the physiologic changes that participate ogy. Tables of normal laboratory values provide a handy
in disease production and occur as a result of disease, as reference of conventional and SI units, as well as conver-
well as the bodys remarkable ability to compensate for sion units.
these changes. The beauty of physiology is that it inte- As with previous editions, every effort has been taken
grates all of the aspects of human genetics, molecular to make the text as accurate and up to date as possible.
and cellular biology, and organ anatomy and physiology This was accomplished through an extensive review of
into a functional whole that can be used to explain both the literature and through the use of critiques provided
the physical and psychological aspects of altered health. by students, faculty, and content specialists. This book
Indeed, it has been my philosophy to share the beauty is an extension of my career and, as such, of my phi-
of the human body and to emphasize that in disease, as losophy. It is my hope that readers will learn to appreci-
in health, there is more going right in the body than ate the marvelous potential of the body, incorporating
is going wrong. it into their own philosophy and ultimately sharing it
With the creation of this text, I focused on present- with their clients.
ing information that is fundamental to understand- Carol M attson Porth
ing the physiologic processes of altered health states;
information that necessary to support an understand-
ing pathophysiology. O ne of the strengths of Essentials A C o m p r e h e n s iv e P a c k a g e f o r
of Pathophysiology is that it is a book to grow with. Te a c h in g a n d Le a r n in g
Although intended as a course textbook for students, To further facilitate teaching and learning, a carefully
it is also designed to serve as a reference book that stu- designed ancillary package has been developed to assist
dents can take with them and use in their practice once faculty and students.
the course is nished.
Updated to re ect state-of-the-art science, content Ins tructo r Re s o urce s
remains organized in a manner that is logical, under- Tools to assist you with teaching your course are avail-
standable, and draws readers into the wonders of the
able upon adoption of this text at http://thePoint.lww.
human body. Concepts build on one another, with con- com/PorthEssentials4e.
cepts from physiology, biochemistry, physics, and other
sciences reviewed as deemed appropriate. A conceptual A thoroughly revised and augmented Test Generator
model that integrates the developmental and preventa- contains more than 1,100 N CLEX-style questions
tive aspects of health has been used. Selection of content mapped to chapter learning objectives.
was based on common health problems, including the An extensive collection of materials is provided for
special needs of children, pregnant women, and elderly each book chapter:
persons. The fourth edition expands the art program, Pre-Lecture Quizzes (and answers) allow you to
increasing the number of photographs depicting clinical check students reading.
manifestations of selected disorders while also provid- PowerPoint Presentations provide an easy way to
ing more than 500 full-color illustrations, many created integrate the textbook with your students class-
speci cally to supplement and expand the concepts pre- room experience; multiple-choice questions are
sented. included to promote class participation.
N ewly created Summary Concepts follow each sec- Guided Lecture N otes offer corresponding
tion and provide a review of material that focuses on PowerPoint slide numbers to simplify preparation
integrating and linking concepts rather than fostering for lecture.
rote memorization. O nce again, the Understanding Discussion Topics (and suggested answers) can be
feature depicts physiologic processes and phenomena, used in the classroom or in online discussion boards
breaking them down into an easy-to-follow sequence to facilitate interaction with your students.


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x Preface

Assignments (and suggested answers) include Adaptive Le arning | Po w e re d by Pre pU

group, written, clinical, and Web assignments to Updated to accompany the 4th edition, Lippincott
engage students in varied activities and assess their Adaptive Learning | Powered by PrepU helps every
learning. student learn more, while giving instructors the data
Case Studies with related questions (and suggested they need to monitor each students progress, strengths,
answers) give students an opportunity to apply their and weaknesses. The adaptive learning system allows
knowledge to a client case similar to one they might instructors to assign quizzes or students to take quizzes
encounter in practice. on their ownquizzes that adapt to each students indi-
A QSEN Competency Map identi es content and spe- vidual mastery level. Visit at http://thePoint.lww.com/
cial features in the book related to competencies iden- PrepU to learn more.
ti ed by the Q SEN Institute.
An Image Bank lets you use the photographs and A Co m pre he ns ive , Dig ital, Inte g rate d Co urs e
illustrations from this textbook in your course
S o lutio n
Strategies for Effective Teaching provide general tips Lippincott CoursePoint is the only integrated digital
for instructors related to preparing course materials course solution for health care education, combining the
and meeting student needs. power of digital course content, interactive resources,
Access to all Student Resources is provided so that and Adaptive Learning | Powered by PrepU. Pulling
you can understand the student experience and use these resources together into one solution, the integrated
these resources in your course as well. product offers a seamless experience for learning, study-
ing, applying, and remediating.
S tude nt Re s o urce s Lippincott CoursePoint provides a personalized
An exciting set of free learning resources is available to learning experience that is structured in the way stu-
help students review and apply vital concepts of patho- dents study. It drives students to immediate remedia-
physiology. For the fourth edition, multimedia engines tion in their text; digital course content and interactive
have been optimized so that students can access many course resources like case studies, videos, and journal
of these resources on mobile devices. Students can acti- articles are also immediately available in the same digi-
vate the codes printed in the front of their textbooks tally integrated course solution to help expand on con-
at http://thePoint.lww.com/activate to access these cepts and bring them to life. After students complete
resources: an adaptive, formative assessment on the reading, the
results identify students speci c weaknesses and, at
Student Review Questions for each chapter, total- the moment its identi ed they dont understand the
ing more than 900 questions, help students review material, they can immediately remediate to that con-
important concepts and practice for certi cation tent. Instructors also have a powerful and measurable
examinations. way to assess their students understanding and to help
Interactive learning resources appeal to a variety of engage them in the course content. Knowing where
learning styles. Icons in the text direct readers to rel- students are struggling allows instructors to adapt class
evant resources: time as appropriate.
Concepts in Action Animations bring physi- Lippincott CoursePoint can bring Adaptive Learn-
ologic and pathophysiologic concepts to life. ing | Powered by PrepU and digital resources together
Interactive Clinical Simulation Case Studies on the same platform to provide all of the aids that
present case scenarios and offer interactive exer- students need to study more effectively, score higher
cises and questions to help students apply what they on exams, and prepare for clinical practice. The
have learned. SmartSense links feature included throughout Course-
Point integrates all of the content, offering immedi-
A SpanishEnglish Audio Glossary provides helpful ate remediation and additional learning resources at
terms and phrases for communicating with patients the click of a mouse. With Lippincott CoursePoint,
who speak Spanish. instructors can collaborate with students at any time,
Journal articles offer access to current articles relevant identify common misunderstandings, evaluate stu-
to each chapter and available in Lippincott Williams dent comprehension, and differentiate instruction as
& Wilkins journals to familiarize students with health needed. This unique offering creates an unparalleled
care literature. learning experience for students because they can
learn and retain course material in an adaptive, per-
S tudy Guide sonalized way.
A comprehensive study aid for reviewing key concepts, Contact your Wolters Kluwer H ealth sales repre-
Study Guide for Porths Essentials of Pathophysiology, sentative or visit http://thePoint.lww.com/coursepoint-
4th edition, has been thoroughly revised and presents a porthessentials4e for more information about Lippincott
variety of exercises, including case studies and practice CoursePoint solution.
N CLEX-style questions, to reinforce textbook content It is with pleasure that we introduce these resources
and enhance learning. the textbook, ancillary resources, and additional

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Preface xi

supplements and learning toolsto you. O ne of our it are important to learn. To help, the G lossary contains
primary goals in creating these resources has been concise de nitions of frequently encountered terms. If
to help students learn how to provide quality care to you are unsure of the meaning of a term you encounter
patients and families across health care settings. We in your reading, check the Glossary in the back of the
hope that we have succeeded in that goal, and we wel- book before proceeding.
come feedback from our readers.
S u m m a ry Co n c e p t s
To t h e Re a d e r Sum m ary concepts at the end of each section provide a
This book was written with the intent of making the review and a reinforcement of the main content that has
subject of pathophysiology an exciting exploration been covered. O ne of the ways to approach learning is
that relates normal body functioning to the physiologic to focus on the major ideas or concepts rather than try-
changes that occur as a result of disease, as well as ing to memorize signi cant amounts of information. As
the bodys remarkable ability to compensate for these you have probably already discovered, it is impossible
changes. Indeed, it is these changes that represent many to memorize everything that is in a particular section or
of the signs and symptoms of disease. chapter of the book. Not only does your brain have a dif-
Using a book such as this can be simpli ed by taking cult time trying to gure out where to store all the differ-
time out to nd what is in the book and how to locate ent bits of information, your brain doesnt know how to
information when it is needed. The Table of Contents retrieve the information when you need it. M ost impor-
provides an overall view of the organization and con- tant of all, memorized lists of content can seldom, if ever,
tent of the book. The Index can be viewed as a road- be applied directly to an actual clinical situation. Sum-
map for locating content. Using the Index, readers can mary concepts guide you in identifying the major ideas or
quickly locate related content in different chapters of concepts that form the foundation for truly understand-
the book or answer questions that come up in other ing the major areas of content. When you understand the
courses. concepts in these sections, you will have a framework for
remembering and using the facts given in the text.
O r g a n iz a t io n
The book is organized into units and chapters. The
units identify broad areas of content, such as altera-
tions in the circulatory system. M any of the units have
introductory chapters that contain information about
the normal structure and function of the body sys-
tems discussed in the unit. These chapters, which are
intended as a review of content from previous courses
as well as an update on recent scienti c advances in
genetic and molecular biology, provide the foundation
for understanding the pathophysiology content pre-
sented in the subsequent chapters. The disorder chap-
ters focus on speci c areas of pathophysiology content,
such as heart failure and circulatory shock. The chap-
ter outline that appears at the beginning of each chap-
ter provides an overall view of the chapter content and
organization. Icons identify speci c content related to
infants and children , pregnant women , and
older adults .

Re a d in g a n d Le a r n in g A id s
In an ever-expanding world of information, you will not
be able to read, let alone remember, everything that is
in this (or any other) book. With this in mind, we have
developed a number of special features that will help
you focus on and master the essential content for your
current as well as future needs. Ta b le s , C h a r t s , a n d Bo x e s
It is essential for any professional to use and
understand the vocabulary of his or her profession. T ables, charts, and box es are designed to present com-
Throughout the text, you will encounter terms in italics. plex information in a format that makes it more mean-
This is a signal that a word and the ideas associated with ingful and easier to remember. Tables have two or more

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x ii Preface

columns, and are often used for the purpose of compar- Illu s t r a t io n s a n d P h o t o g r a p h s
ing or contrasting information. Charts have one column
and are used to summarize information. Boxes highlight The full-color illustrations will help you to build your
key information. own mental image of the content that is being presented.
Each drawing has been developed to fully support and
build upon the ideas in the text. Some illustrations are
used to help you picture the complex interactions of the
multiple phenomena that are involved in the develop-
ment of a particular disease; others can help you visu-
alize normal function or understand the mechanisms
whereby the disease processes exert their effects. In
addition, photographs depicting clinical manifestations
and detailing pathologic processes provide a realistic
view of selected disorders and pathologic processes.

C lin ic a l Fe a t u r e s
This edition retains the illustrations that depict the clini-
cal features of persons with selected diseases. This fea-
ture is designed to help you visualize the entire spectrum
of clinical manifestations that are associated with these
disease states.

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Preface x iii

U n d e r s t a n d in g P h y s io lo g ic P r o c e s s e s are unable to answer a question, reread the relevant sec-

tion in the chapter.
Included in a number of chapters is an Understanding
feature that focuses on the physiologic processes and
phenomena that form the basis for understanding disor-
ders presented in the text. This feature breaks a process
or phenomenon down to its component parts and pres-
ents them in a sequential manner, providing an insight
into the many opportunities for disease processes to dis-
rupt the sequence.

A p p e n d ix
The L ab V alues tables in the appendix provide rapid
M a t e r ia l f o r Re v ie w access to normal values for many laboratory tests in
An important feature has been built into the text to help conventional and SI units, as well as a description of the
you verify your understanding of the material presented. pre xes, symbols, and factors (e.g., micro, , 10 6 ) used
After you have nished reading and studying the chap- for describing these values. Knowledge of normal values
ter, work on answering the R eview Ex ercises at the end can help you put abnormal values in context.
of the chapter. They are designed to help you integrate, We hope that this guide has given you a clear picture of
conceptualize, and apply material from the text. If you how to use this book. Good luck and enjoy the journey!

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Ac kn o w le d g m e n t s
As in past editions, many persons participated in the Sherry Dickinson, executive editor; Dawn Lagrosa, asso-
creation of this work. The contributing authors deserve ciate product development editor; Joan Wendt, design
a special mention. Dr. Gaspard, in particular, deserves coordinator; and M arian Bellus, production project
thanks. H er wide breadth of knowledge and skillful manager. Thanks also to Wendy Beth Jackelow, M FA,
assistance were invaluable in preparing the text and CM I, for her talent and expertise in creating and modi-
developing the illustrations for the book. Another per- fying the illustrations.
son who deserves recognition is Georgianne H eymann, The students in the classes I have taught over the
who assisted in editing the manuscript. As with previous years also deserve a special salute, for they are the inspi-
editions, she provided not only excellent editorial assis- ration upon which this book was founded. They pro-
tance but also encouragement and support when the vided the questions, suggestions, and contact with the
tasks associated with manuscript preparation became real world of patient care that directed the organiza-
most frustrating. I would also like to acknowledge Jody tion and selection of content for the book.
Erickson, RN , BSN , DN P, FN P, BC for her assistance Last, but certainly not least, I would like to acknowl-
with selected work in the text. edge my family and friends for their unlimited patience,
Special thanks also to those at Wolters Kluwer H ealth understanding, and encouragement throughout the
who participated in the development of this edition: entire process.

x iv

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Co n t e n t s
Introduction to Pathophysiology x viii Calcium, Phosphorus, and M agnesium Balance 181
AcidBase Balance 191
U N IT 1 C e ll a n d Tis s u e
Fu n c t io n 1 CHAPTER 9 Stress and Adaptation 206
Stress and Adaptation 206
CHAPTER 1 Cell Structure and Function 1 Disorders of the Stress Response 215
Functional Components of the Cell 1
Cell M etabolism and Energy Storage 8 CHAPTER 10 Disorders of N utritional Status 223
Integration of Cell Function 12 Energetics and N utritional Status 223
Tissues 17 O verweight and O besity 230
Undernutrition and Eating Disorders 234
CHAPTER 2 Cellular Responses to Stress, Injury,
and Aging 31 UNIT 3 He m a t o p o ie t ic Fu n c t io n 241
Cellular Responses to Persistent Stress 31 CHAPTER 11 Disorders of White Blood Cells and
Cell Injury, Death, and Senescence 36 Lymphoid Tissues 241
CHAPTER 3 In ammation, the In ammatory H ematopoietic and Lymphoid Tissues 241
Response, and Fever 49 N onneoplastic Disorders of White Blood Cells 246
General Features of In ammation 49 N eoplastic Disorders of H ematopoietic and
Acute In ammation 53 Lymphoid O rigin 249
Chronic In ammation 61 CHAPTER 12 Disorders of Hemostasis 261
Systemic M anifestations of In ammation 62 H emostasis and Blood Coagulation 261
CHAPTER 4 Cell Proliferation and Tissue H ypercoagulability States 267
Regeneration and Repair 71 Bleeding Disorders 269
Cell Proliferation and Tissue Regeneration 71 CHAPTER 13 Disorders of Red Blood Cells 277
H ealing by Connective Tissue Repair 78 The Red Blood Cell 277
CHAPTER 5 Genetic Control of Cell Function and Anemia 282
Inheritance 87 Polycythemia 291
Genetic Control of Cell Function 87 Age-Related Changes in Red Blood Cells 291
Chromosomes 95
Patterns of Inheritance 98 UN IT 4 In f e c t io n a n d Im m u n it y 297
Gene Technology 99 CHAPTER 14 Mechanisms of Infectious Disease 297
CHAPTER 6 Genetic and Congenital General Concepts of Infectious Diseases 297
Disorders 106 Epidemiology of Infectious Diseases 306
Disorders Involving Single or M ultiple Genes 106 Diagnosis of Infectious Diseases 311
Chromosomal Disorders 115 Treatment of Infectious Diseases 314
Disorders Due to Environmental In uences 120 N ew and Emerging Infectious Diseases 316
Prenatal Screening and Diagnosis 124 CHAPTER 15 Innate and Adaptive Immunity 318
CHAPTER 7 N eoplasia 129 Introduction to the Immune System 318
Characteristics of Benign and M alignant Innate Immunity 325
N eoplasms 129 Adaptive Immunity 331
Etiology of Cancer 137 Developmental Aspects of the Immune System 341
Clinical M anifestations 144 CHAPTER 16 Disorders of the Immune
Screening, Diagnosis, and Treatment 147 Response 344
Childhood Cancers and Late Effects on Cancer H ypersensitivity Disorders 344
Survivors 153 Transplantation Immunopathology 352
Autoimmune Disease 354
U N IT 2 In t e g r a t iv e Bo d y Immunode ciency Disorders 358
Fu n c t io n s 1 5 9
CHAPTER 8 Disorders of Fluid, Electrolyte, and U N IT 5 C ir c u la t o r y Fu n c t io n 375
AcidBase Balance 159 CHAPTER 17 Control of Cardiovascular
Composition and Compartmental Distribution of Function 375
Body Fluids 159 O rganization of the Circulatory System 375
Water and Sodium Balance 167 Principles of Blood Flow 378
Potassium Balance 177 The H eart as a Pump 382

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xvi Contents

The Systemic Circulation and Control of Blood O bstructive Disorders 631

Flow 394 M alignant Tumors of the Kidney 636
CHAPTER 18 Disorders of Blood Flow and Blood CHAPTER 26 Acute Kidney Injury and Chronic
Pressure 402 Kidney Disease 639
Blood Vessel Structure and Function 402 Acute Kidney Injury 639
Disorders of the Arterial Circulation 404 Chronic Kidney Disease 643
Disorders of Arterial Blood Pressure 420 Chronic Kidney Disease in Children and Elderly
Disorders of the Venous Circulation 436 Persons 652
CHAPTER 19 Disorders of Cardiac Function 444 CHAPTER 27 Disorders of the Bladder and Lower
Coronary Artery Disease 444 Urinary Tract 656
Endocardial and Valvular Disorders 457 Control of Urine Elimination 656
Disorders of the Pericardium 465 Disorders of Lower Urinary Tract Structures and
Cardiomyopathies 468 Function 661
H eart Disease in Infants and Children 472 Urinary Tract Infections 667
Cancer of the Bladder 671
CHAPTER 20 Heart Failure and Circulatory
Shock 486 U N IT 8 G a s t r o in t e s t in a l a n d
H eart Failure 486 He p a t o b ilia r y Fu n c t io n 675
Circulatory Failure (Shock) 500
CHAPTER 28 Structure and Function of the
U N IT 6 Re s p ir a t o r y Fu n c t io n 513 Gastrointestinal System 675
O rganization and Function of the Gastrointestinal
CHAPTER 21 Control of Respiratory Function 513
Tract 675
Structural O rganization of the Respiratory
Gastrointestinal Innervation and M otility 680
System 513
Secretory Functions of the Gastrointestinal
Exchange of Gases Between the Atmosphere and the
Tract 686
Lungs 520
Digestion and Absorption in the Gastrointestinal
Exchange of Gases Within the Lungs 528
Tract 689
O xygen and Carbon Dioxide Transport 530
Anorexia, N ausea, and Vomiting 693
Control of Breathing 535
CHAPTER 29 Disorders of Gastrointestinal
CHAPTER 22 Respiratory Tract Infections,
Function 696
N eoplasms, and Childhood
Disorders of the Esophagus 696
Disorders 539
Disorders of the Stomach 701
Respiratory Tract Infections 539
Disorders of the Small and Large Intestines 705
Cancer of the Lung 552
Respiratory Disorders in Children 555 CHAPTER 30 Disorders of Hepatobiliary and
Exocrine Pancreas Function 724
CHAPTER 23 Disorders of Ventilation and Gas
The Liver and H epatobiliary System 724
Exchange 565
Disorders of H epatic and Biliary Function 731
Physiologic Effects of Ventilation and Diffusion
Disorders of the H epatobiliary System and Exocrine
Disorders 565
Pancreas 745
Disorders of Lung In ation 568
O bstructive Airway Disorders 572 U N IT 9 En d o c r in e S y s t e m 753
Interstitial Lung Diseases 586
Disorders of the Pulmonary Circulation 588 CHAPTER 31 Mechanisms of Endocrine
Acute Respiratory Disorders 592 Control 753
The Endocrine System 753
U N IT 7 Kid n e y a n d U r in a r y Tr a c t
CHAPTER 32 Disorders of Endocrine Control of
Fu n c t io n 5 9 9 Growth and Metabolism 767
CHAPTER 24 Structure and Function of the General Aspects of Altered Endocrine
Kidney 599 Function 767
Functional Anatomy of the Kidney 599 Anterior Pituitary and Growth H ormone
Elimination and Endocrine Functions of the Disorders 768
Kidney 611 Thyroid H ormone Disorders 775
Tests of Renal Function 614 Adrenal Cortical H ormone Disorders 783
CHAPTER 25 Disorders of Renal Function 617 CHAPTER 33 Diabetes Mellitus and the Metabolic
Congenital and H ereditary Disorders of the Syndrome 793
Kidney 617 H ormonal Control of N utrient M etabolism and
Disorders of Glomerular Function 621 Storage 793
Tubular and Interstitial Disorders 628 Diabetes M ellitus 799

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Contents x v ii

U N IT 1 0 N e r v o u s S y s t e m 821 Disorders of the Female Reproductive

O rgans 1024
CHAPTER 34 Organization and Control of N eural M enstrual Disorders 1038
Function 821 Disorders of the Breast 1041
N ervous Tissue Cells 821
N erve Cell Communication 825 CHAPTER 41 Sexually Transmitted Infections 1049
Developmental O rganization of the N ervous Infections of the External Genitalia 1050
System 830 Vaginal Infections 1054
Spinal Cord and Brain 837 Vaginal-Urogenital-Systemic Infections 1056
The Autonomic N ervous System 847
U N IT 1 2 M u s c u lo s k e le t a l
CHAPTER 35 Somatosensory Function, Pain, and Fu n c t io n 1 0 6 3
Headache 854
O rganization and Control of Somatosensory CHAPTER 42 Structure and Function of the Skeletal
Function 854 System 1063
Pain Sensation 860 Structures of the Skeletal System 1063
Alterations in Pain Sensitivity and Special Types of Joints 1073
Pain 869 CHAPTER 43 Disorders of the Skeletal System:
H eadache and Associated Pain 872 Trauma, Infections, N eoplasms, and
Pain in Children and O lder Adults 875 Childhood Disorders 1078
CHAPTER 36 Disorders of N euromuscular Injury and Trauma of M usculoskeletal
Function 880 Structures 1078
O rganization and Control of M otor Function 880 Bone Infections and O steonecrosis 1091
Disorders of the M otor Unit 888 N eoplasms 1094
Disorders of the Cerebellum and Basal Ganglia 897 Skeletal Disorders in Children 1098
Upper M otor N euron Disorders 902 CHAPTER 44 Disorders of the Skeletal System:
CHAPTER 37 Disorders of Brain Function 916 Metabolic and Rheumatic
Brain Injury 916 Disorders 1111
Cerebrovascular Disease 930 M etabolic Bone Disease 1111
Infections 940 Rheumatic Disorders 1119
Brain Tumors 942 Rheumatic Diseases in Children and the
Seizure Disorders 945 Elderly 1133
N eurocognitive Disorders 948
U N IT 1 3 In t e g u m e n t a r y
CHAPTER 38 Disorders of Special Sensory Function: Fu n c t io n 1 1 4 1
Vision, Hearing, and Vestibular
Function 955 CHAPTER 45 Structure and Function of the
The Eye and Disorders of Vision 955 Integumentum 1141
The Ear and Disorders of Auditory Function 975 Structure and Function of the Skin 1141
The Vestibular System and Disorders of Appendages of the Skin 1146
Equilibrium 984 M anifestations of Skin Disorders 1148
CHAPTER 46 Disorders of Skin Integrity and
U N IT 11 G e n it o u r in a ry a n d Function 1153
Re p ro d u c t ive Fu n c t io n 993 Primary Disorders of the Skin 1153
CHAPTER 39 Disorders of the Male Genitourinary Skin Disorders Due to Ultraviolet Radiation,
System 993 H eat, and Pressure Injury 1167
Physiologic Basis of M ale Reproductive N evi and Skin Cancers 1173
Function 993 Age-Related Skin Conditions 1177
Disorders of the Penis, the Scrotum and Testes, and G lossary 1185
the Prostate 1000 A ppendix A : L ab V alues 1197
Disorders in Childhood and Aging 1012 Index 1199
CHAPTER 40 Disorders of the Female Genitourinary
System 1017
Structure and Function of the Female Reproductive
System 1017

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In t ro d u c t i o n t o Pa t h o p h y s i o l o g y
Pathophysiology, which is the focus of this book, may in uences, environmental factors (e.g., viral infections
be de ned as the physiology of altered health. The term in the mother, maternal drug use, irradiation, or intra-
combines the words pathology and physiology. Pathol- uterine crowding), or a combination of genetic and envi-
ogy (from the Greek pathos, meaning disease ) deals ronmental factors. A cquired defects are those that are
with the study of the structural and functional changes caused by events that occur after birth. These include
in cells, tissues, and organs of the body that cause or injury, exposure to infectious agents, inadequate nutri-
are caused by disease. Physiology deals with the func- tion, lack of oxygen, inappropriate immune responses,
tions of the human body. Thus, pathophysiology deals and neoplasia. M any diseases are thought to be the
not only with the cellular and organ changes that occur result of a genetic predisposition and an environmental
with disease, but also with the effects that these changes event or events that serve as a trigger to initiate disease
have on total body function. In addition, pathophysiol- development.
ogy focuses on the mechanisms of the underlying disease
process and provides the background for preventive as Patho g e ne s is
well as therapeutic health care measures and practices. Pathogenesis is the sequence of cellular and tissue events
that take place from the time of initial contact with an
D is e a s e etiologic agent until the ultimate expression of a dis-
ease. 2 Etiology describes what sets the disease process
D isease may be de ned as an interruption, cessation, in motion, while pathogenesis describes how the disease
or disorder of a body system or organ structure that is process evolves. Although the two terms often are used
characterized usually by a recognized etiologic agent or interchangeably, their meanings are quite different. For
agents, an identi able group of signs and symptoms, example, atherosclerosis often is cited as the cause or
or consistent anatomic alterations.1 The aspects of the etiology of coronary heart disease. In reality, the pro-
disease process include etiology, pathogenesis, morpho- gression from fatty streak to the occlusive vessel lesion
logic changes, and clinical manifestations. seen in persons with coronary heart disease represents
the pathogenesis of the disorder. The true etiology of
Etio lo g y atherosclerosis remains largely uncertain.
The causes of disease are known as etiologic factors.2
Among the recognized etiologic agents are biologic Mo rpho lo g y
agents (e.g., bacteria, viruses), physical forces (e.g., M orphology refers to the fundamental structure or form
trauma, burns, radiation), chemical agents (e.g., poi- of cells or tissues. M orphologic changes are concerned
sons, alcohol), and nutritional excesses or de cits. At the with both the gross anatomic and microscopic changes
molecular level, it is important to distinguish between that are characteristic of a disease. 2 H istology deals with
abnormal molecules and molecules that cause disease. 3 the study of the cells and extracellular matrix of body
This is true of diseases such as cystic brosis, sickle cell tissues. The most common method used in the study of
anemia, and familial hypercholesterolemia, in which the tissues is the preparation of histologic sectionsthin,
genetic abnormality of a single amino acid, transporter translucent sections of human tissues and organsthat
molecule, or receptor protein produces widespread can be examined with the aid of a microscope. H isto-
effects on health. logic sections play an important role in the diagnosis of
M ost disease-causing agents are nonspeci c, and many types of cancer. A lesion represents a pathologic
many different agents can cause disease of a single or traumatic discontinuity of a body organ or tissue.
organ. A single agent or traumatic event can, how- Descriptions of lesion size and characteristics often can
ever, lead to disease of a number of organs or systems. be obtained through the use of radiographs, ultrasonog-
Although a disease-causing agent can affect more than a raphy, and other imaging methods. Lesions also may be
single organ and a number of disease-causing agents can sampled by biopsy and the tissue samples subjected to
affect the same organ, most disease states do not have a histologic study.
single cause. Instead, the majority of diseases are mul-
tifactorial in origin. This is particularly true of diseases Clinical Manife s tatio ns
such as cancer, heart disease, and diabetes. The multiple Diseases can manifest in a number of ways. Sometimes
factors that predispose to a particular disease often are the condition produces manifestations, such as fever,
referred to as risk factors.4 that make it evident that the person is sick. In other
O ne way to view the factors that cause disease is cases, the condition is silent at the onset and is detected
to group them into categories according to whether during examination for other purposes or after the dis-
they were present at birth or acquired later in life. ease is far advanced.
Congenital conditions are defects that are present at Signs and sym ptom s are terms used to describe the
birth, although they may not be evident until later in structural and functional changes that accompany a dis-
life. Congenital conditions may be caused by genetic ease. 3 A sym ptom is a subjective complaint that is noted

x v iii

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Introduction to Pathophysiology x ix

by the person with a disorder, whereas a sign is a mani- extent to which a measurement tool measures what it is
festation that is noted by an observer. Pain, dif culty in intended to measure. This often is assessed by comparing
breathing, and dizziness are symptoms of a disease. An a measurement method with the best possible method
elevated temperature, a swollen extremity, and changes of measure that is available. For example, the validity
in pupil size are objective signs that can be observed by of blood pressure measurements obtained by a sphyg-
someone other than the person with the disease. Signs momanometer might be compared with those obtained
and symptoms may be related to the primary disorder or by intra-arterial measurements. R eliability refers to the
they may represent the bodys attempt to compensate for extent to which an observation, if repeated, gives the
the altered function caused by the pathologic condition. same result. A poorly calibrated blood pressure machine
M any pathologic states are not observed directlyone may give inconsistent measurements of blood pressure,
cannot see a sick heart or a failing kidney. Instead, what particularly of pressures in either the high or low range.
can be observed is the bodys attempt to compensate for Reliability also depends on the persons making the mea-
changes in function brought about by the disease, such surements. For example, blood pressure measurements
as the tachycardia that accompanies blood loss or the may vary from one observer to another because of the
increased respiratory rate that occurs with pneumonia. technique used (e.g., different observers may de ate the
A syndrom e is a compilation of signs and symptoms cuff at a different rate, thus obtaining different values),
(e.g., chronic fatigue syndrome) that are characteristic the way the numbers on the manometer are read, or dif-
of a speci c disease state. Com plications are possible ferences in hearing acuity.
adverse extensions of a disease or outcomes from treat- In the eld of clinical laboratory measurements, stan-
ment. Sequelae are lesions or impairments that follow or dardization is aimed at increasing the trueness and reli-
are caused by a disease. ability of measured values. Standardization relies on the
use of written standards, reference measurement pro-
Diag no s is cedures, and reference materials. 9 In the United States,
A diagnosis is the designation as to the nature or cause the Food and Drug Administration (FDA) regulates in
of a health problem (e.g., bacterial pneumonia or hem- vitro diagnostic devices, including clinical laboratory
orrhagic stroke). The diagnostic process usually requires instruments, test kits, and reagents. M anufacturers who
a careful history and physical examination. The history propose to market new diagnostic devices must submit
is used to obtain a persons account of his or her symp- information on their instrument, test kit, or reagent to
toms and their progression, and the factors that contrib- the FDA, as required by existing statutes and regulations.
ute to a diagnosis. The physical examination is done to The FDA reviews this information to decide whether the
observe for signs of altered body structure or function. product may be marketed in the United States.
The development of a diagnosis involves weighing M easures of sensitivity and speci city are concerned
competing possibilities and selecting the most likely one with determining how likely or how well the test or
from among the conditions that might be responsible for observation will identify people with or without the dis-
the persons clinical presentation.4 The clinical probabil- ease.4 Sensitivity refers to the proportion of people with
ity of a given disease in a person of a given age, gender, a disease who are positive for that disease on a given test
race, lifestyle, and locality often is in uential in arriving or observation (called a true-positive result). If the result
at a presumptive diagnosis. Laboratory tests, radiologic of a very sensitive test is negative, it tells us the per-
studies, computed tomography (CT) scans, and other son does not have the disease and the disease has been
tests often are used to con rm a diagnosis. excluded or ruled out. Speci city refers to the propor-
An important factor when interpreting diagnostic test tion of people without the disease who are negative on a
results is the determination of whether they are normal given test or observation (called a true-negative result).
or abnormal. Is a blood count above normal, within Speci city can be calculated only from among people
the normal range, or below normal? What is termed a who do not have the disease. A test that is 95% speci c
norm al value for a laboratory test is established statisti- correctly identi es 95 of 100 normal people. The other
cally from test results obtained from a selected sample of 5% are false-positive results. A false-positive test result
people. The normal values refer to the 95% distribution can be unduly stressful for the person being tested,
(mean plus or minus two standard deviations [mean 2 whereas a false-negative test result can delay diagnosis
SD]) of test results for the reference population.46 Thus, and jeopardize the outcome of treatment.
the normal levels for serum sodium (136 to 145 mEq/L) Predictive value is the extent to which an observation
represent the mean serum level for the reference popu- or test result is able to predict the presence of a given
lation 2 SD. The normal values for some laboratory disease or condition.4,10 A positive predictive value refers
tests are adjusted for sex or age. For example, the nor- to the proportion of true-positive results that occurs in
mal hemoglobin range for women is 12.0 to 16.0 g/dL, a given population. In a group of women found to have
and for men, 14.0 to 17.4 g/dL.7 Serum creatinine levels suspect breast nodules in a cancer screening program,
often are adjusted for age in the elderly, and normal the proportion later determined to have breast cancer
values for serum phosphate differ between adults and would constitute the positive predictive value. A nega-
children. tive predictive value refers to the true-negative obser-
The quality of data on which a diagnosis is based vations in a population. In a screening test for breast
may be judged for their validity, reliability, sensitivity, cancer, the negative predictive value represents the pro-
speci city, and predictive value.4,7,8 V alidity refers to the portion of women without suspect nodules who do not

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xx Introduction to Pathophysiology

have breast cancer. Although predictive values rely in for multifactorial diseases, such as heart disease and
part on sensitivity and speci city, they depend more cancer. Epidemiology looks for patterns, such as age,
heavily on the prevalence of the condition in the popu- race, dietary habits, lifestyle, or geographic location,
lation. Despite unchanging sensitivity and speci city, of persons affected with a particular disorder. In con-
the positive predictive value of an observation rises with trast to biomedical researchers, who seek to elucidate
prevalence, whereas the negative predictive value falls. the mechanisms of disease production, epidemiologists
are more concerned with whether something happens
Clinical Co urs e than how it happens. For example, the epidemiologist is
The clinical course describes the evolution of a disease. more concerned with whether smoking itself is related
A disease can have an acute, subacute, or chronic course. to cardiovascular disease and whether the risk of heart
An acute disorder is one that is relatively severe, but self- disease decreases when smoking ceases. The biomedi-
limiting. Chronic disease implies a continuous, long- cal researcher, however, is more concerned about the
term process. A chronic disease can run a continuous causative agent in cigarette smoke and the pathway by
course or can present with exacerbations (aggravation which it contributes to heart disease.
of symptoms and severity of the disease) and remissions M uch of our knowledge about disease comes from
(a period during which there is a decrease in severity and epidemiologic studies. Epidemiologic methods are used
symptoms). Subacute disease is intermediate or between to determine how a disease is spread, how to control it,
acute and chronic: it is not as severe as an acute disease how to prevent it, and how to eliminate it. Epidemio-
and not as prolonged as a chronic disease. logic methods also are used to study the natural history
The spectrum of disease severity for infectious dis- of disease, to evaluate new preventative and treatment
eases, such as hepatitis B, can range from preclinical strategies, to explore the impact of different patterns of
to persistent chronic infection. During the preclinical health care delivery, and to predict future health care
stage, the disease is not clinically evident but is destined needs. As such, epidemiologic studies serve as a basis
to progress to clinical disease. As with hepatitis B, it is for clinical decision making, allocation of health care
possible to transmit a virus during the preclinical stage. dollars, and development of policies related to public
Subclinical disease is not clinically apparent and is not health issues.
destined to become clinically apparent. It is diagnosed M easures of disease frequency are an important aspect
with antibody or culture tests. M ost cases of tubercu- of epidemiology. They establish a means for predicting
losis are not clinically apparent, and evidence of their what diseases are present in a population and provide
presence is established by skin tests. Clinical disease is an indication of the rate at which they are increasing
manifested by signs and symptoms. A persistent chronic or decreasing. A disease case can be either an existing
infectious disease persists for yearssometimes for life. case or the number of new episodes of a particular ill-
Carrier status refers to an individual who harbors an ness that are diagnosed within a given period. Incidence
organism but is not infected, as evidenced by antibody re ects the number of new cases arising in a popula-
response or clinical manifestations. This person still can tion at risk during a speci ed time. The population at
infect others. Carrier status may be of limited duration risk is considered to be persons who are without the
or it may be chronic, lasting for months or years. disease but are at risk for developing it. It is determined
by dividing the number of new cases of a disease by the
P e r s p e c t iv e s a n d P a t t e r n s o f D is e a s e population at risk for development of the disease during
the same period (e.g., new cases per 1000 or 100,000
The health of individuals is closely linked to the health persons in the population who are at risk). The cumula-
of the community and to the population it encompasses. tive incidence estimates the risk of developing the disease
The ability to traverse continents in a matter of hours during that period of time. Prevalence is a measure of
has opened the world to issues of populations at a global existing disease in a population at a given point in time
level. Diseases that once were con ned to limited areas (e.g., number of existing cases divided by the current
of the world now pose a threat to populations through- population). 9 The prevalence is not an estimate of risk of
out the world. developing a disease because it is a function of both new
As we move through the 21st century, we are continu- cases and how long the cases remain in the population.
ally reminded that the health care system and the services Incidence and prevalence are always reported as rates
it delivers are targeted to particular populations. M an- (e.g., cases per 100 or cases per 100,000).
aged care systems are focused on a population-based M orbidity and mortality statistics provide informa-
approach to planning, delivering, providing, and evalu- tion about the functional effects (morbidity) and death-
ating health care. The focus of health care also has begun producing (mortality) characteristics of a disease. These
to emerge as a partnership in which individuals are asked statistics are useful in terms of anticipating health care
to assume greater responsibility for their own health. needs, planning of public education programs, direct-
ing health research efforts, and allocating health care
Epide m io lo g y and Patte rns o f Dis e as e dollars.
Epidem iology is the study of disease occurrence in M ortality statistics provide information about the
human populations.4 It was initially developed to causes of death in a given population. In most countries,
explain the spread of infectious diseases during epidem- people are legally required to record certain facts such
ics and has emerged as a science to study risk factors as age, sex, and cause of death on a death certi cate.

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Introduction to Pathophysiology xxi

Internationally agreed-upon classi cation procedures in 1950, was set up by the U.S. Public H ealth Service
(the International Classi cation of Diseases [ICD] by to study the characteristics of people who would later
the World H ealth O rganization) are used for coding the develop coronary heart disease. The study consisted of
cause of death, and these data are expressed as death 5000 persons, aged 30 to 59 years, selected at random
rates. 11 Crude mortality rates (i.e., number of deaths in and followed for an initial period of 20 years, during
a given period) do not account for age, sex, race, socio- which time it was predicted that 1500 of them would
economic status, and other factors. For this reason, develop coronary heart disease. The advantage of such
mortality often is expressed as death rates for a speci c a study is that it can explore a number of risk factors at
population, such as the infant mortality rate. M ortality the same time and determine the relative importance of
also can be described in terms of the leading causes of each. Another advantage is that the risk factors can later
death according to age, sex, race, and ethnicity. be related to other diseases, such as stroke.
M orbidity describes the effects an illness has on a A second well-known cohort study is the N urses
persons life. M any diseases, such as arthritis, have low H ealth Study, which was developed by H arvard
death rates but a signi cant impact on quality of life. University and Brigham and Womens H ospital. The
M orbidity is concerned not only with the occurrence or study began in 1976 with a cohort of 121,700 female
incidence of a disease but also the persistence and long- nurses, 30 to 55 years of age, living in the United States.13
term consequences of the disease. Initially designed to explore the relationship between
oral contraceptives and breast cancer, nurses in the study
De te rm inatio n o f Ris k Facto rs have provided answers to detailed questions about their
Conditions suspected of contributing to the develop- menstrual cycle, smoking habits, diet, weight and waist
ment of a disease are called risk factors. They may be measurements, activity patterns, health problems, and
inherent to the person (high blood pressure or over- medication use. They have given urine and blood sam-
weight) or external (smoking or drinking alcohol). ples, and even provided researchers with their toenail
There are different types of studies used to determine clippings. In selecting the cohort, it was reasoned that
risk factors, including cross-sectional studies, casecon- nurses would be well-organized, accurate, and observant
trol studies, and cohort studies. Cross-sectional studies in their responses, and that physiologically they would
use the simultaneous collection of information neces- be no different from other groups of women. It also was
sary for classi cation of exposure and outcome status. anticipated that their childbearing, eating, and smok-
They can be used to compare the prevalence of a disease ing patterns would be similar to those of other working
in those with the factor (or exposure) with the preva- women.
lence of a disease in those who are unexposed to the
factor, such as the prevalence of coronary heart disease Natural His to ry
in smokers and nonsmokers. Casecontrol studies are The natural history of a disease refers to the progression
designed to compare persons known to have the out- and projected outcome of the disease without medical
come of interest (cases) with those known not to have intervention. 4 By studying the patterns of a disease over
the outcome of interest (controls).4 Information on time in populations, epidemiologists can better under-
exposures or characteristics of interest is then collected stand its natural history. Knowledge of the natural his-
from persons in both groups. For example, the char- tory can be used to determine disease outcome, establish
acteristics of maternal alcohol consumption in infants priorities for health care services, determine the effects
born with a fetal alcohol spectrum disorder (cases) can of screening and early detection programs on disease
be compared with those in infants born without one of outcome, and compare the results of new treatments
these disorders (controls). with the expected outcome without treatment.
A cohort is a group of persons who were born at There are some diseases for which there are no effec-
approximately the same time or share some characteris- tive treatment methods available, or for which the cur-
tics of interest.4 Persons enrolled in a cohort study (also rent treatment measures are only effective in certain
called a longitudinal study) are followed over a period people. In this case, the natural history of the disease
of time to observe a speci c health outcome. A cohort can be used as a predictor of outcome. For example, the
may consist of a single group of persons chosen because natural history of hepatitis C indicates that 80% of peo-
they have or have not been exposed to suspected risk ple who become infected with the virus fail to clear the
factors; two groups speci cally selected because one has virus and progress to chronic infection.14 Information
been exposed and the other has not; or a single exposed about the natural history of a disease and the availabil-
group in which the results are compared with the gen- ity of effective treatment methods provides directions for
eral population. preventive measures. In the case of hepatitis C, careful
O ne of the best-known examples of a cohort study screening of blood donations and education of intrave-
is the Framingham Study, which was carried out in nous drug abusers can be used to prevent transfer of the
Framingham, M assachusetts. 12 Framingham was virus. At the same time, scientists are striving to develop
selected because of the size of its population, the relative a vaccine that will prevent infection in persons exposed
ease with which the people could be contacted, and the to the virus. The development of vaccines to prevent the
stability of the population in terms of moving into and spread of infectious diseases such as polio and hepatitis
out of the area. This longitudinal study, which began B undoubtedly has been motivated by knowledge about

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x x ii Introduction to Pathophysiology

the natural history of these diseases and the lack of effec- interventions that prevent further deterioration or
tive intervention measures. With other diseases, such as reduce the complications of a disease once it has been
breast cancer, early detection through use of clinical diagnosed.
breast examination and mammography increases the
chances for a cure.
Prognosis refers to the probable outcome and pros-
pect of recovery from a disease. It can be designated as REFEREN CES
chances for full recovery, possibility of complications,
or anticipated survival time. Prognosis often is presented 1. Stedm ans M edical D ictionary. 28th ed. Philadelphia, PA:
in relation to treatment optionsthat is, the expected Lippincott Williams & Wilkins; 2006:855.
outcomes or chances for survival with or without a cer- 2. Kumar V, Abbas AK, Fausto N , et al. R obbins and Cotran
tain type of treatment. The prognosis associated with a Pathologic Basis of D isease. 8th ed. Philadelphia, PA:
given type of treatment usually is presented along with Saunders Elsevier; 2012:4,5.
3. Waldenstrom J. Sick molecules and our concepts of illness.
the risk associated with the treatment. J Intern M ed. 1989;225:221227.
4. Fletcher RH , Fletcher SW, Fletcher G. Clinical Epidem iology:
Le ve ls o f Pre ve ntio n T he Essentials. 5th ed. Philadelphia, PA: Wolters Kluwer
Leading a healthy life contributes to the prevention of H ealth/Lippincott Williams & Wilkins; 2014:116, 1729,
disease. There are three fundamental types of preven- 3149, 5059, 93104, 108130.
tion: primary prevention, secondary prevention, and ter- 5. Brigden M L, H eathcote JC. Problems with interpreting labo-
tiary prevention. 4,15 It is important to note that all three ratory tests. Postgrad M ed. 2000;107(7):145162.
levels are aimed at prevention. Prim ary prevention is 6. M ayer D. Essentials of Evidence-Based M edicine. N ew York,
directed at keeping disease from occurring by removing N Y: Cambridge University Press; 2004.
7. Fischbach F, Dunning M B. A M anual of L aboratory and
all risk factors. Examples of primary prevention include D iagnostic Tests. 8th ed. Philadelphia, PA: Wolters Kluwer
the administration of folic acid to pregnant women and H ealth/Lippincott Williams & Wilkins; 2009;74:964.
women who may become pregnant to prevent fetal neu- 8. Dawson B, Trapp RG, Trapp R. Basic and Clinical
ral tube defects, giving immunizations to children to Biostatistics. N ew York, N Y: Lange M edical Books/
prevent communicable disease, and counseling people M cGraw-H ill; 2004.
to adopt healthy lifestyles as a means of preventing 9. M ichaud GY. The role of standards in the development and
heart disease. Primary prevention is often accomplished implementation of clinical laboratory tests: A domestic and
outside the health care system at the community level. global perspective. Cancer Biom ark . 2005;1:209216.
Some primary prevention measures are mandated by 10. M ontori VM , Wyer P, N ewman TB, et al. Tips for learning
law (e.g., wearing seat belts in automobiles and helmet of evidence-based medicine: 5. The effect of spectrum of
disease on performance of diagnostic tests. Can M ed A ssoc J.
use on motorcycles). O ther primary prevention activi- 2005;173:385390.
ties (e.g., use of earplugs or dust masks) occur in speci c 11. World H ealth O rganization. About WH O : De nition of
occupations. Secondary prevention detects disease early health; disease eradication/elimination goals. 2007. Available
when it is still asymptomatic and treatment measures at: http://www.who.int/about/de nition/en/. Accessed
can affect a cure or stop the disease from progressing. September 2, 2013.
The use of a Papanicolaou (Pap) smear for early detec- 12. Framingham H eart Study. Framingham H eart Study:
tion of cervical cancer is an example of secondary pre- Design, rationale, objectives, and research milestones.
vention. Screening also includes history taking (asking if 2011. Available at: http://www.framinghamheartstudy.org.
a person smokes), physical examination (blood pressure Accessed September 2, 2013.
measurement), laboratory tests (cholesterol level deter- 13. Channing Laboratory. N urses H ealth Study. 2011. Available
at: http://www.channing.harvard.edu/nhs/. Accessed
mination), and other procedures (colonoscopy) that can September 2, 2013.
be applied to asymptomatic people. M ost secondary 14. Liang J, Reherman B, Seeff LB, et al. Pathogenesis, natural
prevention is done in clinical settings. All types of health history, treatment, and prevention of hepatitis C. A nn Intern
care professionals (e.g., p hysicians, nurses, dentists, M ed. 2000;132:296305.
audiologists, optometrists) participate in secondary 15. N eis M A, M cEwan M . Com m unity H ealth N ursing. 5th ed.
prevention. T ertiary prevention is directed at clinical St. Louis, M O : M osby; 2011:190.

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C e ll a n d Tis s u e
Fu n c t io n

Functiona l Components of the Cell
The Cell Membra ne
The N ucleus C h a p t e r
The Cytopla sm a nd Its Membra ne-Bound
O rga nelles
Ribosomes, Endopla smic Reticulum, a nd Golgi
Appa ra tus
Peroxisomes Ce ll S t r u c t u re
Protea somes
The Cytoskeleton
a n d Fu n c t io n
Actin Micro la ments a nd Intermedia te
Fila ments
Cell Meta bolism a nd Energy Stora ge
Ana erobic Meta bolism
T he cell is the smallest functional unit of life. Cells are
the smallest unit capable of self-reproduction and
are vehicles for transmitting genetic information that
Aerobic Meta bolism de nes the organism. Cells with similar specialized func-
Integra tion of Cell Function tions are often organized into larger functional aggre-
Cell Signa ling a nd Communica tion Mecha nisms gates called tissues. These tissues in turn combine to
Cell Surfa ce Receptors form the various body structures and organs. Although
Intra cellula r Receptors the cells of different tissues and organs vary in structure
Membra ne Tra nsport Mecha nisms and function, they are remarkably similar in their abil-
Diffusion ity to exchange materials with their immediate environ-
ment, obtain energy from organic nutrients, synthesize
Active Tra nsport
complex molecules, and replicate themselves. Because
Vesicula r Tra nsport
most diseases begin at the cellular level, an understand-
G enera tion of Membra ne Potentia ls ing of cell function is crucial to understanding the dis-
Tissues ease process. Some diseases affect the cells of a single
Embryonic O rigin of Tissue Types organ, others affect the cells of a particular tissue type,
Epithelia l Tissue and still others affect the cells of the entire organism.
Simple Epithelium This chapter discusses the structural and functional
Stra ti ed a nd Pseudostra ti ed Epithelium components of the cell, basic cellular mechanisms, and
G la ndula r Epithelium tissue types.
Epithelia l Cell Renewa l
Connective Tissue
Loose Connective Tissue
Fu n c t io n a l C o m p o n e n t s o f
Adipose Tissue t h e C e ll
Reticula r a nd Dense Connective Tissue
Although diverse in their organization, all eukaryotic
Muscle Tissue
cells (cells with a true nucleus) have in common struc-
Skeleta l Muscle tures that perform unique functions. Under a light micro-
Smooth Muscle scope, three primary components of the eukaryotic cell
N ervous Tissue become evident: the plasma membrane, the nucleus, and
Extra cellula r Tissue Components the cytoplasm, while numerous structures are visible by
Cell Junctions higher magni cation electron microscopy (Fig. 1-1).
Extra cellula r Ma trix
Cell Adhesion Molecules 1

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2 U N I T 1 Cell and Tissue Function



S e cre tory
ve s icle s
Nucle a r
pore s
a ppa ra tus

Nucle olus

Fre e
Nucle a r e nve lope
ribos ome s
s urrounding nucle us
P e roxis ome
e ndopla s mic Microtubule
re ticulum

Lys os ome
Ce ll
me mbra ne

FIG U RE 1-1. Co m p o s ite ce ll

Chroma tin d e s ig n e d to s h o w in o n e ce ll a ll
S mooth o f th e va rio u s co m p o n e n ts o f
e ndopla s mic re ticulum th e n u cle u s a n d cyto p la s m .

Two distinct regions exist in the cell: the cytoplasm , carbohydrates, and proteins (Fig. 1-2). A main struc-
which lies outside the nucleus, and the nucleoplasm , tural component of the membrane is its lipid bilayer that
which lies inside the nucleus. The cytoplasm contains consists primarily of phospholipids, cholesterol, and
membrane-enclosed organelles ( little organs ) and glycoproteins. This lipid bilayer provides the basic uid
inclusions in an aqueous gel called the cytoplasm ic structure of the membrane and serves as a relatively
m atrix . The matrix consists of a variety of solutes includ- impermeable barrier to all but lipid-soluble substances.
ing inorganic ions (N a +, K+, Ca +) and organic molecules The most abundant lipids are phospholipids, each with
such as intermediate metabolites, carbohydrates, lipids, a hydrophilic (water-soluble) head and a hydrophobic
proteins, and RN A. The nucleus is the largest organelle (water-insoluble) tail. Phospholipid molecules along
within the cell and its nucleoplasm contains the genome with the glycolipids are aligned such that their hydro-
along with the enzymes necessary for deoxyribonucleic philic heads face outward on each side of the membrane
acid (DN A) and ribonucleic acid (RN A) transcription. and their hydrophobic tails project toward the middle
of the membrane. The presence of cholesterol makes the
membrane regionally less deformable and less perme-
Th e C e ll M e m b r a n e able to small water soluble molecules.
Although the lipid bilayer provides the basic struc-
In many respects, the cell membrane (also called the ture of the cell membrane, proteins carry out most of the
plasma membrane) is one of the most important parts speci c functions. The integral proteins span the entire
of the cell. It acts as a semipermeable structure that sep- lipid bilayer and are part of the membrane. Because
arates the intracellular and extracellular environments. most of the integral proteins pass directly through the
It controls the transport of materials from the extracel- membrane, they are also referred to as transm em brane
lular uids to the interior of the cell, holds and binds proteins. O ther proteins, called the peripheral proteins,
receptors for hormones and other biologically active are bound to one or the other side of the membrane and
substances, participates in the generation and conduc- do not pass into the lipid bilayer.
tion of electrical currents in nerve and muscle cells, and The manner in which proteins are associated with the
aids in the regulation of cell growth and proliferation. cell membrane often determines their function. Thus,
The cell membrane is a dynamic and uid struc- peripheral proteins are associated with functions involv-
ture consisting of an organized arrangement of lipids, ing the inner or outer side of the membrane where they

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C H A P T E R 1 Cell Structure and Function 3

Hydrophilic pola r he a d

Chole s te rol
Extra c e llu la r
Pore flu id
mole cule
Ca rbohydra te
Hydrophobic Glycoprote in
fa tty a cid cha in

P hos pholipids :
Pola r he a d

Fa tty a cid ta ils

Cyto s o l
Cha nne l Pe riphe ra l
prote in prote in
Fila me nts of
cytos ke le ton Tra ns me mbra ne
Chole s te rol prote in
FIG U RE 1-2 . S tru ctu re o f th e p la s m a (ce ll) m e m b ra n e s h o w in g th e hyd ro p h ilic (p o la r) h e a d s a n d
th e hyd ro p h o b ic (fa tty a cid ) ta ils (in s e t), a n d th e p o s itio n o f th e in te g ra l a n d p e rip h e ra l p ro te in s in
re la tio n to th e in te rio r a n d e xte rio r o f th e ce ll.

are found. Several peripheral proteins serve as receptors stay alive. The genes also represent the individual units
or are involved in intracellular signaling systems. By of inheritance that transmit information from one gen-
contrast, only the transmembrane proteins can function eration to another. The nucleus also is the site for the
on both sides of the membrane or transport molecules synthesis of the three types of RN A that move to the
across it. M any integral transmembrane proteins form cytoplasm and carry out the actual synthesis of pro-
the ion channels found on the cell surface. These chan- teins. M essenger RN A (mRN A) copies and carries the
nel proteins have a complex morphology and are selec- DN A instructions for protein synthesis to the cyto-
tive with respect to the substances they transmit. plasm; ribosomal RN A (rRN A) is the site of protein
A fuzzy-looking layer, called the cell coat or glycoca- synthesis; and transfer RN A (tRN A) transports amino
lyx , surrounds the cell surface. It consists of long, com- acids to the site of protein synthesis for incorporation
plex carbohydrate chains attached to protein molecules into the protein being synthesized (see Chapter 5).
that penetrate the outside portion of the membrane The complex structure of DN A and DN A-associated
(i.e., glycoproteins); outward-facing membrane lipids proteins dispersed in the nuclear matrix is called
(i.e., glycolipids); and carbohydrate-binding proteins chrom atin. Depending on its transcriptional activ-
called lectins. The cell coat participates in cell-to-cell ity, chromatin may be condensed as an inactive form
recognition due to antigens that label cells as self or of chromatin called heterochrom atin or extended as a
nonself and are important in tissue transplantation. The more active form called euchrom atin. Because hetero-
cell coat of a red blood cell contains the ABO blood chromatic regions of the nucleus stain more intensely
group antigens. than regions consisting of euchromatin, nuclear stain-
ing can be a guide to cell activity. The nucleus also con-
tains the darkly stained round body called the nucleolus
Th e N u c le u s that is the site of rRN A synthesis and initial ribosomal
assembly. Cells that are actively synthesizing proteins
The nucleus of a nondividing cell appears as a rounded can be recognized because their nucleoli are large and
or elongated structure situated near the center of the cell prominent and the nucleus as a whole is euchromatic or
(see Fig. 1-1). It is enclosed in a nuclear envelope and slightly stained.
contains chromatin, the genetic material of the nucleus, Surrounding the nucleus is the nuclear envelope
and a distinct region called the nucleolus. All eukaryotic formed by an inner and outer nuclear membrane con-
cells have at least one nucleus (prokaryotic cells, such as taining a perinuclear space between them (Fig. 1-3). The
bacteria, lack a nucleus and nuclear membrane). inner nuclear membrane is supported by a rigid network
The nucleus is regarded as the control center for the of protein laments called nuclear lam ina that bind to
cell. It contains the DN A that is essential to the cell chromosomes and secure their position in the nucleus.
because its genes encode the information necessary for The outer nuclear membrane resembles and is continu-
the synthesis of proteins that the cell must produce to ous with the membrane of the endoplasmic reticulum.

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4 U N I T 1 Cell and Tissue Function

Rough ER Fre e ribos ome s

Ma trix Ribos ome s
Nucle a r Tra ns fe r ve s icle
Pe rinucle a r
pore s s pa ce S e cre tory
gra nule s

Oute r nucle a r
me mbra ne
Inne r nucle a r
me mbra ne

Nucle a r
la mina Rough e ndopla s mic
re ticulum
S mooth ER Golgi a ppa ra tus
Tubula r e le me nts
FIG U RE 1-3 . Sch e m a tic d ra w in g o f th e in n e r a n d o u te r
of the ER
m e m b ra n e s o f th e n u cle a r e nve lo p e . Th e d o u b le -m e m b ra n e
e nve lo p e is p e n e tra te d b y p o re s in w h ich n u cle a r p o re FIG U RE 1-4 . Th re e -d im e n s io n a l vie w o f th e ro u g h a n d th e
co m p le xe s a re p o s itio n e d a n d co n tin u o u s w ith th e ro u g h s m o o th e n d o p la s m ic re ticu la (ER) a n d th e Go lg i a p p a ra tu s .
e n d o p la s m ic re ticu lu m . Th e n u cle a r la m in a o n th e s u rfa ce o f Th e ER fu n ctio n s a s a tu b u la r co m m u n ica tio n s ys te m
th e in n e r m e m b ra n e b in d s to DNA a n d h o ld s th e ch ro m o s o m e s th ro u g h w h ich s u b s ta n ce s ca n b e tra n s p o rte d fro m o n e p a rt
in p la ce . DNA, d e o xyrib o n u cle ic a cid . o f th e ce ll to a n o th e r a n d a s th e s ite o f p ro te in (ro u g h ER),
ca rb o hyd ra te , a n d lip id (s m o o th ER) s yn th e s is . Mo s t o f th e
p ro te in s s yn th e s ize d b y th e ro u g h ER a re s e a le d in to tra n s fe r
ve s icle s a n d tra n s p o rte d to th e Go lg i a p p a ra tu s , w h e re th e y a re
At the site where the inner and outer membranes fuse, m o d i e d a n d p a cka g e d in to s e cre to ry g ra n u le s .
the nuclear envelope is penetrated by pores containing
nuclear pore com plex es. Structures of the nuclear pore
complexes act as barriers and enable selective transpor- Ribo s o m e s . The ribosomes are small particles of
tation of RN A, ribosomes, and lipids and proteins with nucleoproteins (rRN A and proteins) that are held
signaling functions between the nucleus and cytoplasm together by a strand of mRN A. Poly Ribosomes exist as
to coordinate events such as gene transcription and met- isolated clusters of free ribosomes within the cytoplasm
abolic activities. or attached to the membrane of the ER (see Fig. 1-4).
Free ribosomes are involved in the synthesis of pro-
teins that remain in the cell as cytoplasmic structural or
Th e Cy t o p la s m a n d It s M e m b r a n e - functional elements, whereas those attached to the ER
Bo u n d O r g a n e lle s translate mRN As that code for proteins to be bound in
The cytoplasm surrounds the nucleus, and it is in membranes or destined for secretion.
the cytoplasm that the work of the cell takes place.
Embedded in the cytoplasm are various membrane- Endo plas m ic Re ticulum . The endoplasmic reticulum is
enclosed organelles (e.g., endoplasmic reticulum [ER], an extensive dynamic system of interconnected membra-
Golgi apparatus, mitochondria, and lysosomes) and nous tubes and sac-like cisternae (see Figs. 1-3 and 1-4).
complexes without membranes (e.g., ribosomes and Within the lumen of the ER is a matrix that connects
proteasomes) that have important functions in cells. the space between the two membranes of the nuclear
envelope to the cell periphery. The ER functions as a
Ribo s o m e s , Endo plas m ic Re ticulum , and tubular communication system for transporting various
substances from one part of the cell to another. A large
Go lg i Apparatus
surface area and multiple enzyme systems attached to
The endoplasmic reticulum (with its associated ribo- the ER membranes also provide the machinery for many
somes) and Golgi apparatus represent the primary sites cellular metabolic functions.
of protein synthesis in the cell (Fig. 1-4). Following Two forms of ER exist in cells: rough and smooth.
protein synthesis in the ribosomes, the endoplasmic R ough ER is studded with ribosomes attached to speci c
reticulum and Golgi apparatus use transport vesicles binding sites on the membrane. These ribosomes, with
to move newly synthesized proteins, membrane com- their accompanying strand of mRN A, synthesize pro-
ponents, and soluble molecules from one organelle teins destined to be incorporated into cell membranes,
to another. used in the generation of lysosomal enzymes, or exported

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C H A P T E R 1 Cell Structure and Function 5

from the cell. The sm ooth ER is free of ribosomes and A B

is continuous with the rough ER. It does not participate Ba cte rium
in protein synthesis; instead, its enzymes are involved in
the synthesis of lipid and steroid hormone molecules, Endocytotic
regulation of intracellular calcium, and metabolism and ve s icle
detoxi cation of certain hormones and drugs. The sar-
coplasmic reticulum of skeletal and cardiac muscle cells
is a form of smooth ER. Calcium ions needed for muscle Ea rly
contraction are stored and released from cisternae of the e ndos ome
sarcoplasmic reticulum. The smooth ER of the liver is
involved in glycogen storage and metabolism of lipid-
soluble drugs. P ha gos ome
La te
e ndos ome
Go lg i Apparatus . The Golgi apparatus, sometimes
called the G olgi com plex , consists of stacks of thin,
attened vesicles or sacs (see Fig. 1-4). These Golgi a ppa ra tus
bodies are found near the nucleus and function in
association with the ER. Substances produced in the Lys os ome P ha golys os ome
ER are transported to the Golgi complex in small,
membrane-bound transport vesicles. M any cells syn- C
Autopha gos ome
thesize proteins that are larger than the active prod- Lipofus cin
uct. The Golgi complex modi es these substances and gra nule s
packages them into secretory granules or vesicles.
Insulin, for example, is synthesized as a large, inac-
tive proinsulin molecule that is cleaved to produce a Autopha golys os ome
smaller, active insulin molecule within the Golgi com- RER Re s idua l
plex of the beta cells of the pancreas. In addition to Mitochondrion body
producing secretory granules, the Golgi complex is
thought to produce large carbohydrate molecules that Exocytos is
are added to proteins produced by the rough ER to FIG U RE 1-5 . Pa th wa ys fo r d ig e s tio n o f m a te ria ls b y
form glycoproteins. lys o s o m e s . (A) Re ce p to r-m e d ia te d e n d o cyto s is w ith fo rm a tio n
o f lys o s o m e fro m e a rly a n d la te e n d o s o m e s . Ve s icle co n te n ts
a re s o rte d in th e e a rly e n d o s o m e w ith re ce p to rs a n d lip id s
Lys o s o m e s b e in g s e n t b a ck to th e m e m b ra n e . Tra n s p o rt ve s icle s ca rry
lys o s o m a l e n zym e s to th e la te e n d o s o m e s , co nve rtin g th e m
The lysosomes, which can be viewed as digestive organ-
in to lys o s o m e s th a t d ig e s t p ro te in s a n d o th e r co m p o n e n ts
elles in the cell, are small, membrane-bound sacs lled a cq u ire d fro m th e e n d o cyto tic ve s icle s . (B) Ph a g o cyto s is
with hydrolytic enzymes. These enzymes can break invo lvin g th e d e live ry o f la rg e e xtra ce llu la r p a rticle s s u ch a s
down excess and worn-out cell parts as well as foreign b a cte ria a n d ce llu la r d e b ris to th e lys o s o m e s via p h a g o s o m e s .
substances that are taken into the cell. All of the lyso- (C) Au to p h a g y is th e p ro ce s s in w h ich w o rn -o u t m ito ch o n d ria
somal enzymes are acid hydrolases, which means that a n d o th e r ce ll p a rts a re s u rro u n d e d b y a m e m b ra n e d e rive d
they require an acid environment. The lysosomes pro- fro m th e ro u g h e n d o p la s m ic re ticu lu m (RER). Th e re s u ltin g
vide this environment by maintaining a pH of approxi- a u to p h a g o s o m e th e n fu s e s w ith a lys o s o m e to fo rm a n
mately 5.0 in their interior. The pH of the cytosol and a u th o p h a g o lys o s o m e . Un d ig e s te d m a te ria l m a y b e e xtru d e d
other cellular components is approximately 7.2. Like all fro m th e ce ll o r re m a in in th e cyto p la s m a s lip o fu s cin g ra n u le s
o r m e m b ra n e -b o u n d re s id u a l b o d ie s .
other cellular organelles, lysosomes not only contain a
unique collection of enzymes, but also have a unique
surrounding membrane that prevents the release of its
digestive enzymes into the cytosol. Depending on the nature of the substance, differ-
Lysosomes are formed from digestive vesicles called ent pathways are used for lysosomal degradation of
endosom es. These vesicles fuse to form multivesicu- unwanted materials (see Fig. 1-5). Small extracellu-
lar bodies called early endosom es (Fig. 1-5). The early lar particles such as extracellular proteins and plasma
endosomes mature into late endosom es as they recycle membrane proteins form endocytotic vesicles after being
lipids, proteins, and other membrane components back internalized by pinocytosis or receptor-mediated endo-
to the plasma membrane in vesicles called recycling ves- cytosis. These vesicles are converted into early and late
icles. Lysosomal enzymes are synthesized in the rough endosomes, after which they mature into lysosomes.
ER and then transported to the Golgi apparatus, where Large extracellular particles such as bacteria, cell debris,
they are biochemically modi ed and packaged for trans- and other foreign particles are engulfed in a process
port to the endosomes. The late endosomes mature into called phagocytosis. A phagosom e, formed as the mate-
lysosomes as they progressively accumulate newly syn- rial is internalized within the cell, fuses with a lysosome
thesized acid hydrolases from the Golgi apparatus and to form a phagolysosom e. Intracellular particles, such
attain digestive abilities. as entire organelles, cytoplasmic proteins, and other

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6 U N I T 1 Cell and Tissue Function

cellular components, are engulfed in a process called Mito cho ndria

autophagy. These particles are isolated from the cyto-
plasmic matrix by ER membranes to form an autopha- The mitochondria are literally the power plants of the
gosom e, which then fuses with a lysosome to form an cell because they contain the enzymes needed for cap-
autophagolysosom e. turing most of the energy in foodstuffs and converting
Although the lysosomal enzymes can break down most it into cellular energy. This multistep process requires
proteins, carbohydrates, and lipids to their basic con- oxygen and is often referred to as aerobic m etabolism .
stituents, some materials remain undigested. These undi- M uch of this energy is stored in the high-energy phos-
gested materials may remain in the cytoplasm as residual phate bonds of adenosine triphosphate (ATP) that serves
bodies or be extruded from the cell. In some long-lived to power various cell activities. M itochondria are found
cells, such as neurons and heart muscle cells, large quan- close to the site of energy consumption in the cell (e.g.,
tities of residual bodies accumulate as lipofuscin granules near the myo brils in muscle cells). The number of mito-
or age pigments. O ther indigestible pigments, such as chondria in a given cell type is largely determined by the
inhaled carbon particles and tattoo pigments, also accu- type of activity the cell performs and how much energy
mulate and may persist in residual bodies for decades. is needed to undertake the activity. For example, a dra-
Lysosomes are also repositories where cells accumu- matic increase in mitochondria occurs in skeletal muscle
late abnormal substances that cannot be completely repeatedly stimulated to contract.
digested or broken down. In some genetic diseases The mitochondria are composed of two membranes:
known as lysosom al storage diseases, a speci c lyso- an outer membrane that encloses the periphery of the
somal enzyme is absent or inactive, in which case the mitochondrion and an inner membrane that forms
digestion of certain cellular substances (e.g., glucocer- shel ike projections, called cristae (Fig. 1-6). The nar-
ebrosides, gangliosides, sphingomyelin) does not occur. row space between the outer and inner membranes is
As a result, these substances accumulate in the cell. In called the interm em brane space, whereas the large space
Tay-Sachs disease (see Chapter 6), an autosomal reces- enclosed by the inner membrane is termed the m atrix
sive disorder, hexosaminidase A, which is the lysosomal space. The outer mitochondrial membrane contains a
enzyme needed for degrading the GM 2 ganglioside found large number of transmembrane porins, through which
in nerve cell membranes, is absent. Although the GM 2 inorganic ions and metabolites may pass. The inner
ganglioside accumulates in many tissues, such as the membrane contains the respiratory chain enzymes and
heart, liver, and spleen, its accumulation in the nervous transport proteins needed for the synthesis of ATP.
system and retina of the eye causes the most damage. M itochondria contain their own DN A and ribosomes
and are self-replicating. The DN A is found in the mito-
Pe roxis o m e s chondrial matrix and is distinct from the chromosomal
DN A found in the nucleus. M itochondrial DN A, known
Spherical membrane-bound organelles called perox i- as the other human genome, is a double-stranded,
som es contain enzymes that are used in oxidative reac- circular molecule that encodes the rRN A and tRN A
tions. Reactions occurring in peroxisomes use oxygen required for intramitochondrial synthesis of the proteins
to produce peroxides and convert hydrogen peroxide needed for the energy-generating function of the mito-
to water. Unless degraded, these highly unstable reac- chondria. Although mitochondrial DN A directs the syn-
tive oxygen species and free radicals (see Chapter 2) thesis of 13 of the proteins required for mitochondrial
would damage other cellular molecules and structures. function, the DN A of the nucleus encodes the structural
Peroxisomes also contain the enzymes needed for break-
ing down verylong-chain fatty acids, which are ineffec-
tively degraded by mitochondrial enzymes. In liver cells, Oute r limiting
peroxisomal enzymes are involved in the formation of me mbra ne
the bile acids.

Pro te as o m e s
Cris ta e
Proteasomes are cytoplasmic protein complexes that are
not bound by membranes. Proteasomes are responsible
for proteolysis of malformed and misfolded proteins and
have roles in many cellular responses and events. The Ma trix
process of cytosolic proteolysis is carefully controlled by s pa ce
the cell and requires that the protein be targeted for deg-
radation. This process involves ubiquitination, a pro-
cess whereby several small ubiquitin molecules (a small
76-amino-acid polypeptide chain) are attached to an Inne r limiting
me mbra ne
amino acid residue of the targeted protein. O nce a pro-
tein is so tagged, it is degraded by proteasomes. After the FIG U RE 1-6 . Mito ch o n d rio n . Th e in n e r m e m b ra n e fo rm s
targeted protein has been degraded, the resultant amino tra n s ve rs e fo ld s ca lle d cris ta e , w h e re th e e n zym e s n e e d e d fo r
acids join the intracellular pool of free amino acids and th e n a l s te p in a d e n o s in e trip h o s p h a te (ATP) p ro d u ctio n (i.e .,
the ubiquitin molecules are released and recycled. o xid a tive p h o s p h o ryla tio n ) a re lo ca te d .

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C H A P T E R 1 Cell Structure and Function 7

proteins of the mitochondria and other proteins needed Ce ll me mbra ne

to carry out cellular respiration. Mitochondrion
M itochondrial DN A is inherited matrilineally (i.e., Microtubule
from the mother) and provides a basis for familial lin-
e ndopla s mic
eage studies. M utations have been found in each of the re ticulum
mitochondrial genes, and an understanding of the role
of mitochondrial DN A in certain diseases and of mech-
anisms to maintain the integrity of the mitochondrial
genome is beginning to emerge. M ost tissues in the
body depend to some extent on oxidative metabolism
and can therefore be affected by mitochondrial DN A
M itochondria also function as key regulators of apop-
tosis or programmed cell death (discussed in Chapter 2).
The initiation of the mitochondrial pathway for apopto-
sis results from an increase in mitochondrial membrane
permeability and the subsequent release of proapoptotic
molecules into the cytoplasm. O ne of these proapoptotic
molecules, cytochrome c, is well known for its role in
cellular respiration. In the cytosol, cytochrome c binds
to a protein called the apoptosis protease activating
factor-1 protein, initiating the molecular events involved
in the apoptosis cascade. O ther apoptotic proteins also
enter the cytoplasm, where they bind to and neutralize
the various apoptotic inhibitors, whose normal func- Nucle us
tion consists of blocking the apoptotic cascade. Both
Microfila me nt Ribos ome s
the formation of reactive oxygen species (e.g., peroxide)
and the activation of the p53 tumor-suppressor gene by
DN A damage or other means initiate apoptotic signal- Inte rme dia te
fila me nts
ing through the mitochondria. Dysregulated apoptosis
(too little or too much) has been implicated in a wide FIG U RE 1-7. Th re e -d im e n s io n a l vie w o f th e n e tw o rk o f
range of diseases, including cancer, in which there is an m icro tu b u le s , m icro la m e n ts , a n d in te rm e d ia te la m e n ts th a t
s u p p o rts th e o rga n e lle s w ith in th e ce ll cyto p la s m .
inappropriately low rate of apoptosis, and neurodegen-
erative diseases, in which there is an increased or exces-
sive rate of apoptosis.
Removal of mucus from the respiratory passages is
highly dependent on the proper functioning of the cilia.
Th e Cy t o s k e le t o n Flagella form the tail-like structures that provide motil-
ity for sperm. Centrioles are small, barrel-shaped bod-
In addition to its organelles, the cytoplasm contains a
ies oriented at right angles to each other. In dividing
network of microtubules, micro laments, and interme-
cells, the two cylindrical centrioles form the mitotic
diate laments (Fig. 1-7). Because they control cell shape
spindle that aids in the separation and movement of the
and movement, these structures are a major component
chromosomes during cell division.
of the structural elements called the cytosk eleton.
Abnormalities of the microtubules occur in a number
of pathologic states. These abnormalities may be mani-
Micro tubule s
fested by an abnormal appearance and function, aber-
M icrotubules are slender and rigid tubular structures rant movements of intracellular organelles, and defective
composed of globular proteins called tubulin. Each cell locomotion. Defective organization of the microtu-
microtubule consists of parallel proto laments, each bules can cause sterility by inhibiting sperm motility, as
composed of - and -tubulin dimers. M icrotubules well as defective motility of cilia in the epithelial lining
function in many ways, including the development and of the respiratory tract, resulting in chronic respiratory
maintenance of cell form; participation in intracellular tract infections. Proper functioning of the microtubules
transport mechanisms, including axoplasmic trans- is also essential for various stages of leukocyte migra-
port in neurons; and formation of the basic structure tion. Drugs that bind to tubulin molecules and prevent
for several complex cytoplasmic organelles, includ- their assembly of microtubules (colchicine) are useful in
ing the cilia, agella, and centrioles. Cilia and agella the treatment of gout, in which symptoms are due to
are microtubule- lled cellular extensions extending movement of leukocytes toward urate crystals in the tis-
from the cell membrane that are capable of sweeping sues. Since microtubules form the mitotic spindle, which
movements. Cilia are found on the apical (luminal) is essential for cell proliferation, drugs that bind micro-
surfaces of many epithelial linings, including the nasal tubules (e.g., vinca alkaloids) are useful in the treatment
sinuses and passages of the upper respiratory system. of cancer.

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8 U N I T 1 Cell and Tissue Function

Actin Micro lam e nts and Inte rm e diate

Filam e nts in th e ce ll. Th e e n d o p la s m ic re ticu lu m (ER)
fu n ctio n s a s a tu b u la r co m m u n ica tio n s ys te m
In addition to microtubules, two other cytoskeletal th ro u g h w h ich s u b s ta n ce s ca n b e tra n s p o rte d
structures exist: micro laments and intermediate la- fro m o n e p a rt o f th e ce ll to a n o th e r a n d a s th e
ments. M icro laments are composed of actin, whereas
s ite o f p ro te in (ro u g h ER), ca rb o hyd ra te , a n d
intermediate laments are a heterogeneous group of
laments with diameter sizes between those of microtu- lip id (s m o o th ER) s yn th e s is . Th e Go lg i a p p a ra tu s
bules and actin laments. m o d i e s m a te ria ls s yn th e s ize d in th e ER a n d
Actin, which can exist in globular and lamentous p a cka g e s th e m in to s e cre to ry g ra n u le s fo r
forms, is of central importance to cellular biology. It tra n s p o rt w ith in th e ce ll o r e xp o rt fro m th e ce ll.
contributes to cell motility, positioning of organelles in Lys o s o m e s , w h ich ca n b e vie w e d a s th e d ig e s tive
the cell, and cell shape and polarity. M any functions of s ys te m o f th e ce ll, co n ta in hyd ro lytic e n zym e s
actin laments are performed in association with myo- th a t d ig e s t w o rn -o u t ce ll p a rts a n d fo re ig n
sin motor proteins. Contractile activities involving actin m a te ria ls . Th e m ito ch o n d ria s e rve a s p o w e r p la n ts
micro laments and associated thick myosin laments fo r th e ce ll b e ca u s e th e y tra n s fo rm fo o d e n e rg y
contribute to muscle contraction. in to ATP, w h ich is u s e d to p o w e r ce ll a ctivitie s .
The intermediate laments include the cytokeratins,
Th e y co n ta in th e ir o w n e xtra ch ro m o s o m a l DNA,
vimentin, and neuro laments. They have structural
and maintenance functions that are important in tissue, w h ich is u s e d in th e s yn th e s is o f ce rta in p ro te in s
cellular, developmental, and differentiation processes. re q u ire d fo r m ito ch o n d ria l fu n ctio n .
They are also very responsive to cellular stresses, such In a d d itio n to its o rga n e lle s , th e cyto p la s m
as heat, radiation, toxins, pathogens and oxidation. a ls o co n ta in s a n e tw o rk o f m icro tu b u le s , a ctin
N euro brillary tangles found in the brain in Alzheimer m icro la m e n ts , a n d in te rm e d ia te la m e n ts
disease contain microtubule-associated proteins and ca lle d th e cyto s ke le to n . Micro tu b u le s a re s le n d e r,
neuro laments, evidence of a disrupted neuronal
s tiff tu b u la r s tru ctu re s th a t in u e n ce ce ll s h a p e ,
p rovid e a m e a n s o f m ovin g o rga n e lle s th ro u g h
th e cyto p la s m , a n d fo rm cilia , a g e lla , a n d
ce n trio le s . Actin m icro la m e n ts a re d yn a m ic,
S U M M A R Y C O N C EP TS th in , th re a d like cyto p la s m ic s tru ctu re s th a t
a re im p o rta n t in ce ll m ove m e n t a n d o rga n e lle
p o s itio n in g . Ma ny typ e s o f in te rm e d ia te la m e n ts
Ce lls a re th e s m a lle s t fu n ctio n a l u n it o f th e fu n ctio n in s u p p o rtin g a n d m a in ta in in g th e s h a p e
b o d y. Th e y a re a u to n o m o u s u n its th a t co n ta in o f ce lls a n d p a rticip a te in n u m e ro u s ce llu la r
s tru ctu re s th a t a re s trikin g ly s im ila r to th o s e p ro ce s s e s .
n e e d e d to m a in ta in to ta l b o d y fu n ctio n .
Th e ce ll m e m b ra n e is a p ro te in -s tu d d e d lip id
b ila ye r th a t s u rro u n d s th e ce ll a n d s e p a ra te s
it fro m its s u rro u n d in g e xte rn a l e nviro n m e n t.
It co n ta in s re ce p to rs fo r h o rm o n e s a n d o th e r C e ll M e t a b o lis m a n d En e r g y
b io lo g ica lly a ctive s u b s ta n ce s , p a rticip a te s in th e S t o ra g e
e le ctrica l e ve n ts th a t o ccu r in n e rve a n d m u s cle
ce lls , a n d a id s in th e re g u la tio n o f ce ll g ro w th Energy metabolism refers to the chemical processes
a n d p ro life ra tio n . Th e ce ll s u rfa ce is s u rro u n d e d involved in converting carbohydrates, fats, and pro-
b y a fu zzy-lo o kin g la ye r ca lle d th e ce ll co a t o r teins from the foods we eat into the energy needed
g lyco ca lyx. Th e ce ll co a t p a rticip a te s in ce ll-to -ce ll for cell functions. Cells use oxygen to transform the
re co g n itio n a n d a d h e s io n , a n d it co n ta in s tis s u e breakdown products of the foods we eat into the
tra n s p la n t a n tig e n s . energy needed for muscle contraction; the transport
of ions and other molecules across cell membranes;
Th e n u cle u s is th e co n tro l ce n te r fo r th e ce ll. It and the synthesis of enzymes, hormones, and other
co n ta in s d e oxyrib o n u cle ic a cid (DNA), w h ich macromolecules.
p ro vid e s th e in fo rm a tio n n e ce s s a ry fo r th e The special unit of currency for transferring energy
s yn th e s is o f th e va rio u s p ro te in s th a t th e ce ll in living cells is ATP. Adenosine triphosphate molecules
m u s t p ro d u ce to s ta y a live a n d to tra n s m it consist of adenosine, a nitrogenous base; ribose, a ve-
in fo rm a tio n fro m o n e g e n e ra tio n to a n o th e r. carbon sugar; and three phosphate groups (Fig. 1-8). The
last two phosphate groups are attached to the remainder
Th e cyto p la s m co n ta in s th e ce lls o rga n e lle s . of the molecule by two high-energy bonds. Each bond
Rib o s o m e s s e rve a s s ite s fo r p ro te in s yn th e s is releases a large amount of energy when hydrolyzed.
Adenosine triphosphate is hydrolyzed to form adenosine

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C H A P T E R 1 Cell Structure and Function 9

High-e ne rgy bonds Ade nine

O- P O P O P O CH2 A P P P
O- O- O- O ATP
Nutrie nt
H H Ene rgy us e d
me ta bolis m
Ribos e s uga r ADP
FIG U RE 1-8 . Ad e n o s in e trip h o s p h a te (ATP) is th e m a jo r s o u rce o f ce llu la r e n e rg y. (A) Ea ch m o le cu le
o f ATP co n ta in s tw o h ig h -e n e rg y b o n d s , e a ch co n ta in in g a b o u t 12 kca l o f p o te n tia l e n e rg y. (B) Th e
h ig h -e n e rg y ATP b o n d s a re in co n s ta n t u x. Th e y a re g e n e ra te d b y s u b s tra te (g lu co s e , a m in o a cid ,
a n d fa t) m e ta b o lis m a n d a re co n s u m e d a s th e e n e rg y is e xp e n d e d . ADP, a d e n o s in e d ip h o s p h a te .

diphosphate (ADP) with the loss of one high-energy acid is reversible, and once the oxygen supply has been
bond and to adenosine monophosphate (AM P) with the restored, lactic acid is converted back to pyruvic acid
loss of two such bonds. The energy liberated from the and used directly for energy or to synthesize glucose.
hydrolysis of ATP is used to drive reactions that require
free energy, such as muscle contraction and active trans-
port mechanisms. Energy from foodstuffs is used to con- Ae ro b ic M e t a b o lis m
vert ADP back to ATP. H ence ATP is often called the
Aerobic metabolism, which supplies 90% of the bodys
energy currency of the cell; energy can be saved or
energy needs, occurs in the cells mitochondria and requires
spent using ATP as an exchange currency.
oxygen. It is here that the hydrogen and carbon molecules
Two types of energy production are present in the
from dietary fats, proteins, and carbohydrates are broken
cell: the anaerobic (i.e., without oxygen) glycolytic path-
down and combined with molecular oxygen to form car-
way, occurring in the cytoplasm, and the aerobic (i.e.,
bon dioxide and water as energy is released. Unlike lactic
with oxygen) pathway, occurring in the mitochondria.
acid, which is an end product of anaerobic metabolism,
The glycolytic pathway serves as the prelude to the aero-
carbon dioxide and water are relatively harmless and eas-
bic pathway.
ily eliminated from the body. In a 24-hour period, oxida-
tive metabolism produces 150 to 300 mL of water.
The citric acid cycle, sometimes called the tricar-
A n a e ro b ic M e t a b o lis m box ylic acid (TCA) or Krebs cycle, provides the nal
Glycolysis is the anaerobic process by which energy common pathway for the metabolism of nutrients. In
is liberated from glucose. It is an important source of the citric acid cycle, which takes place in the matrix of
energy for cells that lack mitochondria. The process also the mitochondria, an activated two-carbon molecule
provides a temporary source of energy for cells that are of acetyl-coenzyme A (acetyl-CoA) condenses with a
deprived of an adequate supply of oxygen. Glycolysis four-carbon molecule of oxaloacetic acid and moves
involves a sequence of reactions that convert glucose to through a series of enzyme-mediated steps. This pro-
pyruvic acid, with the concomitant production of ATP cess produces hydrogen atoms and carbon dioxide.
from ADP. The net gain of energy from the glycolytic As hydrogen is generated, it combines with N AD +
metabolism of one molecule of glucose is two ATP mol- or avin adenine dinucleotide (FAD) for transfer to
ecules. Although relatively inef cient as to energy yield, the electron transport system. Besides pyruvate from
the glycolytic pathway is important during periods of the glycolysis of glucose, products of amino acid and
decreased oxygen delivery, such as occurs in skeletal fatty acid degradation enter the citric acid cycle and
muscle during the rst few minutes of exercise. contribute to the generation of ATP.
Glycolysis requires the presence of nicotinamide O xidation of electrons from the hydrogen atoms
adenine dinucleotide (N AD +), a hydrogen carrier. The generated during glycolysis and the citric acid cycle
end products of glycolysis are pyruvate and N ADH (the takes place in the electron transport system located
reduced form of N AD +) plus H +. When oxygen is pres- on the inner mitochondrial membrane. The elec-
ent, pyruvic acid moves into the aerobic mitochondrial trons are used to reduce elemental oxygen, which
pathway, and N AD + is regenerated as N ADH delivers combines with hydrogen to form water. During this
its electron and proton (H +) to the oxidative electron sequence of oxidative reactions, large amounts of
transport system. Under anaerobic conditions, such as energy are released and used to convert ADP to ATP.
cardiac arrest or circulatory shock, pyruvic acid is con- Because the formation of ATP involves the addition of
verted to lactic acid, which diffuses out of the cells into a high-energy phosphate bond to ADP, the process is
the extracellular uid. Conversion of pyruvate to lactic called ox idative phosphorylation.
(tex t continues on page 12)

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10 U N I T 1 Cell and Tissue Function

U N D E R S TA N D IN G Ce ll Me ta b o lis m
Cell m etabolism is the process that converts dietary fuels from carbohydrates,
proteins, and fats into adenosine triphosphate (ATP), which provides energy
for the cell. Adenosine triphosphate is form ed through three m ajor pathways:
(1) the glycolytic pathway, (2) the citric acid cycle, and (3) the electron transport
chain. In fuel m etabolism , which is an oxidationreduction reaction, the fuel
donates electrons and is oxidized, and the coenzym es nicotinam ide adenine
dinucleotide (NAD) and avin adenine dinucleotide (FAD) accept electrons and
are reduced.

1 C O
Gly c o ly t ic P a t h w a y. Glycolysis,
which occurs in the cytoplasm of the C C
cell, involves the splitting of the six- C C
carbon glucose molecule into two 1 Glucos e
three-carbon molecules of pyruvic
acid. Because the reaction that splits 2 ATP
glucose requires two molecules of
ATP, there is a net gain of only two
2 ADP + 2 P
molecules of ATP from each mol-
ecule of glucose that is metabolized.
The process is anaerobic and does
not require oxygen (O 2 ) or produce
carbon dioxide (CO 2 ). When O 2 is 2 NAD+ 4 ADP + 4 P
present, pyruvic acid moves into
the mitochondria, where it enters
2 NADH + 2H+ 4 ATP
the aerobic citric acid cycle. Under
anaerobic conditions, pyruvate is
La ctic a cid
converted to lactic acid, allowing (a na e robic)
glycolysis to continue as a means of
supplying cells with ATP when O 2 is P yruvic a cid
lacking. (a e robic)

P yruvic a cid

Ace tyl-coe nzyme A
Cit r ic Ac id Cy c le . Under aerobic To e le ctron
conditions, both of the pyruvic acid tra ns port
molecules formed by the glycolytic cha in
pathway enter the mitochondria, NADH + H+
where each combines with acetyl-
coenzyme to form acetyl-coenzyme
A (acetyl-CoA). The formation of FADH2
acetyl-CoA begins the reactions that
occur in the citric acid cycle. Some
reactions release CO 2 and some Citric a cid
transfer electrons from the hydrogen
atom to N ADH or FADH . In addi- NADH
tion to pyruvic acid from the glycol- CO 2
CO 2 + H+
ysis of glucose, fatty acid and amino ATP
acid breakdown products can also
enter the citric acid cycle. Fatty acids,
which are the major source of fuel in NADH + H+
the body, are oxidized by a process To e le ctron
tra ns port
called -ox idation to acetyl-CoA for cha in
entry into the citric acid cycle.

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C H A P T E R 1 Cell Structure and Function 11

3 Inte rme mbra ne
Ele c t ro n Tr a n s p o r t Ch a in . At s pa ce
the completion of the citric acid
cycle, each glucose molecule has Inne r me mbra ne
yielded only four new molecules of
ATP (two from glycolysis and two Oute r me mbra ne
from the citric acid cycle). In fact, Ma trix
the principal function of these ear-
lier stages is to make the electrons
(e) from glucose and other food
substrates available for oxidation.
O xidation of the electrons carried Oute r me mbra ne
by N ADH and FADH 2 is accom- ATP s ynthe s is
plished through a series of enzy- H+ H+ H+
matically catalyzed reactions in the
mitochondrial electron transport
chain. During these reactions, pro- Inne r me mbra ne
tons (H +) combine with O 2 to form Ma trix
water (H 2 O ), and large amounts of e- O
energy are released and used to add H+ +
a high-energy phosphate bond to 2 H2 O Pi
adenosine diphosphate (ADP), con- Ele ctron-tra ns port cha in H+
verting it to ATP. There is a net yield
of 36 molecules of ATP from 1 mol-
ecule of glucose (2 from glycolysis,
2 from the citric acid cycle, and 32
from the electron transport chain).
In general, the net amount of ATP
formed from each gram of protein
that is metabolized is less than for
glucose, whereas that obtained from
fat is greater (e.g., each 16-carbon
fatty acid molecule yields about 129
molecules of ATP).

S U M M A R Y C O N C EP TS th e cyto p la s m a n d th e a e ro b ic p a th w a ys in
th e m ito ch o n d ria . Th e m o s t e f cie n t o f th e s e
p a th w a ys is th e a e ro b ic citric a cid cycle a n d
Me ta b o lis m is th e p ro ce s s w h e re b y th e e le ctro n tra n s p o rt ch a in in th e m ito ch o n d ria .
ca rb o hyd ra te s , fa ts , a n d p ro te in s fro m th e fo o d s
Th is p a th w a y, w h ich re q u ire s o xyg e n , p ro d u ce s
w e e a t a re b ro ke n d o w n a n d s u b s e q u e n tly
ca rb o n d io xid e a n d w a te r a s e n d p ro d u cts
co nve rte d in to th e e n e rg y n e e d e d fo r ce ll
a n d re s u lts in th e re le a s e o f la rg e a m o u n ts
fu n ctio n . En e rg y is s to re d in th e h ig h -e n e rg y
o f e n e rg y th a t is u s e d to co n ve rt a d e n o s in e
p h o s p h a te b o n d s o f a d e n o s in e trip h o s p h a te
d ip h o s p h a te (ADP) to ATP. Th e g lyco lytic
(ATP), w h ich s e rve s a s th e e n e rg y cu rre n cy fo r
p a th w a y in th e cyto p la s m in vo lve s th e
th e ce ll.
b re a kd o w n o f g lu co s e to fo rm ATP. Th is p a th w a y
Tw o s ite s o f e n e rg y co n ve rs io n a re p re s e n t ca n fu n ctio n w ith o u t o xyg e n b y p ro d u cin g la ctic
in ce lls : th e a n a e ro b ic g lyco lytic p a th w a y in a cid .

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12 U N I T 1 Cell and Tissue Function

(tex t continued from page 9)

In t e g r a t io n o f C e ll Fu n c t io n (Firs t me s s e nge r)

Within a complex organism, such as a human being, dif- Am p lifie r En zym e

ferent organs, tissues, and individual cell types develop spe- Extra ce llula r
Ade nyl cycla s e
cialized functions and needs. Yet each cell must contribute
to the integrated life process as the body grows, differenti-
ates, and adapts to changing conditions. Such integration Re ce ptor
requires that cells have the ability to communicate with one
another, transport substances between their intracellular Intra ce llula r
and extracellular environments, and generate and respond G prote in
to changes in the electrical charge of membrane potentials. (Tra ns duce r)

C e ll S ig n a lin g a n d C o m m u n ic a t io n
P hos phoryla te d S e cond me s s e nge r
M e c h a n is m s pre curs or
Signaling systems consist of receptors that reside either ATP
on the cell membrane (surface receptors) or within the
cells (intracellular receptors). Receptors are activated by Intra ce llula r e ffe ctor
a variety of chemical messengers including neurotrans-
mitters, hormones, growth factors, and other chemical
messengers, as well as signaling proteins called cyto- Ce ll re s pons e
k ines and lipids. Some lipid-soluble chemical messengers
FIG U RE 1-9 . Activa tio n o f a G-p ro te in -lin ke d re ce p to r a n d
move through the membrane and bind to cytoplasmic
p ro d u ctio n o f cyclic a d e n o s in e m o n o p h o s p h a te (cAMP).
or nuclear receptors to exert their physiologic effects. Bin d in g o f a h o rm o n e (th e rs t m e s s e n g e r) ca u s e s th e
Signaling systems often rely on the intermediary activity a ctiva te d re ce p to r to in te ra ct w ith th e in a ctive , g u a n in e
of a separate class of membrane-bound regulatory pro- d ip h o s p h a te (GDP)-b o u n d G p ro te in . Th is re s u lts in a ctiva tio n
teins to convert extracellular signals, or rst messengers, o f th e G p ro te in a n d d is s o cia tio n o f th e G p ro te in , , a n d
into intracellular signals, or second messengers, such s u b u n its . Th e a ctiva te d s u b u n it o f th e G p ro te in ca n th e n
as a unique form of adenosine monophosphate called in te ra ct w ith a n d a ctiva te th e m e m b ra n e p ro te in a d e nyl cycla s e
cyclic adenosine m onophosphate (cAM P). M any mol- to ca ta lyze th e co nve rs io n o f a d e n o s in e trip h o s p h a te (ATP)
ecules involved in signal transduction within cells are to th e s e co n d m e s s e n g e r cAMP. Th e s e co n d m e s s e n g e r th e n
enzymes and other proteins. Some of the enzymes are a ctiva te s a n in te rn a l e ffe cto r, w h ich le a d s to th e ce ll re s p o n s e .
protein kinases that catalyze the phosphorylation of
proteins, thereby changing their activity and function. which recognizes a speci c ligand or rst messenger. Upon
ligand-binding, they all undergo conformational changes
that activate the G protein found on the cytoplasmic side
Ce ll S urface Re ce pto rs of the cell membrane (Fig. 1-9). All G proteins incorpo-
Each cell type in the body contains numerous receptor rate the guanosine triphosphatase (GTPase) cycle, which
proteins, which as a set may characterize the cell type, functions as a molecular switch that exists in two states:
that enable it to respond to a complementary set of an activated (on) state and an inactivated (off) state.
ligands (i.e., molecules with a high af nity for a recep- Receptor activation causes the subunit to dissociate
tor) or signaling molecules in a speci c, preprogrammed from the receptor and the and subunits and transmit
way. These receptors, which span the cell membrane, the signal from the rst messenger to a membrane-bound
relay information to a series of intracellular interme- intermediate called an effector. Often, the effector is an
diates that eventually pass the signal to its nal des- enzyme that converts an inactive precursor molecule into
tination. There are three major classes of cell surface a second messenger, which diffuses into the cytoplasm and
receptor proteins: G proteinlinked receptors, enzyme- carries the signal beyond the cell membrane. O ne com-
linked receptors, and ion channellinked receptors. mon effector is the enzyme adenylyl cyclase, which con-
verts the precursor ATP to the second messenger cAM P,
G Pro te inLinke d Re ce pto rs . G proteinlinked recep- transferring the two phosphate groups to other proteins.
tors mediate cellular responses for numerous types of This transfer changes the conformation and function of
rst messengers through regulatory proteins called G these proteins. Such changes eventually produce the cell
proteins that bind to guanine nucleotides such as guanine response initiated by the rst messenger, whether it is a
diphosphate (GDP) and guanine triphosphate (GTP). secretion, muscle contraction or relaxation, or change in
With more than 1000 members, G proteinlinked recep- metabolism. Sometimes it is the opening of membrane
tors are the largest family of cell surface receptors. channels involved in calcium or potassium in ux.
Although there are differences among the G protein
linked receptors, all share a number of features. They all Enzym e -Linke d Re ce pto rs . Like G proteinlinked
have a ligand-binding extracellular receptor component, receptors, enzyme-linked receptors are transmembrane

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C H A P T E R 1 Cell Structure and Function 13

Cha nne l Ca rrie r

prote in prote in
bilaye r
Conce ntra tion
gra die nt


Diffus ion Diffus ion Fa cilita te d

through through a diffus ion
lipid bilaye r cha nne l

Pa s s ive tra ns port Active tra ns port Ve s icula r tra ns port

FIG U RE 1-1 0 . Me ch a n is m s o f m e m b ra n e tra n s p o rt. Pa s s ive tra n s p o rt re p re s e n ts th e n e t m o ve m e n t
fro m a re g io n o f h ig h e r to lo w e r co n ce n tra tio n a n d a ctive tra n s p o rt (e n e rg y re q u irin g ) fro m a re g io n
o f lo w e r to h ig h e r co n ce n tra tio n . Ve s icu la r tra n s p o rt invo lve s th e fo rm a tio n o f m e m b ra n e -e n clo s e d
ve s icle s o r s a cs th a t s e rve a s tra n s p o rt ve h icle s fro m e xtra ce llu la r m a te ria ls th a t a re b e in g m o ve d
in to th e ce ll (e n d o cyto s is ) o r in tra ce llu la r m a te ria ls th a t a re b e in g m ove d o u t o f th e ce ll (e xo cyto s is ).
ADP, a d e n o s in e d ip h o s p h a te ; ATP, a d e n o s in e trip h o s p h a te .

proteins with their ligand-binding site on the outer surface uids, while allowing a few lipid-soluble (e.g., alco-
of the cell membrane. Instead of having a cytosolic domain hols with lower numbers of hydrocarbons, oxygen,
that associates with a G protein, their cytosolic domain nitrogen) and uncharged molecules (glycerol, water) to
either has intrinsic enzyme activity or associates directly cross the cell membrane by simple diffusion. The cell
with an enzyme. There are several classes of enzyme- membrane also contains large numbers of protein mol-
linked receptors, including one widely used in hormonal ecules, many of which insert completely through the
control of cell function. The binding of the hormone to membrane (Fig. 1-10). M ost ions and small molecules
a special transmembrane receptor results in activation of rely on these proteins for transport.
the enzyme adenylyl cyclase at the intracellular portion of Different membrane proteins function in different
the receptor. This enzyme then catalyzes the formation of ways. For example, channel proteins form water-lined
the second messenger cAM P, which has multiple effects passageways through the membrane and allow free
on cell function. Insulin, for example, acts by binding to movement of water as well as selected ions or molecules.
an enzyme-linked receptor (see Chapter 33). M em brane transport proteins bind molecules or ions and
undergo a series of conformational changes to transfer
Ion ChannelLinked Receptors. Ion channellinked the bound solute across the membrane. Some transport
receptors are involved in the rapid synaptic signaling proteins, called uniporters, simply mediate the move-
between electrically excitable cells. Many neurotransmit- ment of a single solute from one side of the membrane
ters mediate this type of signaling by transiently opening to the other, whereas others function as coupled trans-
or closing ion channels formed by integral proteins in the porters in which the transfer of one solute depends on
cell membrane (to be discussed). This type of signaling is the transfer of a second solute (Fig. 1-11). This coupled
involved in the transmission of impulses in nerve and mus- transport involves either the simultaneous transport in
cle cells. the same direction, performed by transporters called
sym porters, or the transport of a second solute in the
Intrace llular Re ce pto rs opposite direction, by transporters called antiporters.
All channels and many transporters allow solutes to
Some messengers, such as thyroid hormone and steroid
cross the membrane only passively by passive transport
hormones, do not bind to membrane receptors but move
or facilitated diffusion. Cells also require transport pro-
directly across the lipid bilayer of the cell membrane and
teins that actively pump certain solutes across the mem-
are transported to the cell nucleus, where they in uence
brane against an electrochemical gradient, in a process
DN A activity (see Chapter 31). M any of these hormones
called active transport. Active transport is directional
bind to a receptor within the cytoplasm, and the receptor
and requires an energy source such as ATP. The cell mem-
hormone complex enters the nucleus. There it binds to
brane can also engulf substances, forming a membrane-
DN A, initiating processes that increase the production
bound vesicle; this vesicle is brought into the cell by
of proteins that alter cell function.
endocytosis. The process by which cellular vesicles fuse
to the cell membrane releasing contents outside of the
M e m b r a n e Tr a n s p o r t M e c h a n is m s cell is called ex ocytosis.
M any integral transmembrane proteins form the ion
The lipid layer of the cell membrane serves as a bar- channels found on the cell surface. These channel pro-
rier against the movement of water and water-soluble teins have a complex morphology and are selective with
substances between the intracellular and extracellular respect to the substances that can transverse the channel.

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14 U N I T 1 Cell and Tissue Function

S Na +
S Na +
Extra ce llula r Extra ce llula r

Intra ce llula r Intra ce llula r

A S ymporte r S Na + B Antiporte r S Na +
FIG U RE 1-11. Se co n d a ry a ctive tra n s p o rt s ys te m s . (A) Sym p o rt o r co tra n s p o rt ca rrie s th e tra n s p o rte d
s o lu te (S ) in th e s a m e d ire ctio n a s th e s o d iu m (Na +) io n . (B) An tip o rt o r co u n te rtra n s p o rt ca rrie s th e
s o lu te a n d Na + in th e o p p o s ite d ire ctio n .

A host of genetic disorders known as channelopathies outer surface, are carried across the membrane attached
involve mutations in channel proteins. For example, to the transporter, and then are released. In facilitated
in cystic brosis (see Chapter 23), the primary defect diffusion, a substance can move only from an area of
resides in an abnormal chloride channel, which results higher concentration to one of lower concentration. The
in increased sodium and water reabsorption that rate at which a substance moves across the membrane
causes respiratory tract secretions to thicken and by facilitated diffusion depends on the difference in con-
occlude the airways. centration between the two sides of the membrane. Also
important are the availability of transport proteins and
Diffus io n the rapidity with which they can bind and release the
substance being transported. It is thought that insulin,
Diffusion refers to the passive process by which mol- which facilitates the movement of glucose into cells, acts
ecules and other particles in a solution become widely by increasing the availability of glucose transporters in
dispersed and reach a uniform concentration because of the cell membrane.
energy created by their spontaneous kinetic movements.
In the process of reaching a uniform concentration, Ion Channels and Gates . Ion channels (leak channels)
these molecules and particles move downhill from are integral proteins that span the width of the membrane
an area of higher to an area of lower concentration. If and are normally composed of several polypeptides or
the molecules or particles carry a net charge, both the protein subunits that form a gating system (Fig. 1-12).
concentration gradient and the electrical potential dif- Speci c stimuli cause the protein subunits to undergo
ference across the membrane in uence transport. conformational changes to form an open channel or gate
Lipid-soluble molecules, such as oxygen, carbon through which the ions can move. In this way, ions do not
dioxide, alcohol, and fatty acids, become dissolved need to cross the lipid-soluble portion of the membrane
in the lipid matrix of the cell membrane and diffuse but can remain in the aqueous solution that lls the ion
through the membrane in the same manner that diffu- channel. M any of the ion channels are highly selective for
sion occurs in water. O ther substances diffuse through transport of one or more speci c ions or molecules. This
minute pores of the cell membrane. selectivity results from the characteristics of the channel
itself, such as its diameter, its shape, and the nature of elec-
S im ple Diffus io n. Simple diffusion means that the trical charges and chemical bonds along its inside surface.
kinetic movement of molecules or ions occurs through The cell membrane contains two basic groups of ion
a membrane opening or through intermolecular spaces channels: leakage channels and gated channels. Leakage
without any interaction with a carrier protein. The rate channels are open even in the unstimulated state,
of diffusion depends on how many particles are avail- whereas gated channels open and close in response to
able for diffusion, the kinetic movement of the particles, speci c stimuli. Three main types of gated channels
and the number and size of the openings in the mem- are present in the cell membrane: voltage-gated chan-
brane through which the molecules or ions can move. nels, which have electrically operated channels that
open when the membrane potential changes beyond a
Facilitate d Diffus io n. Like simple diffusion, facilitated certain point; ligand-gated channels, which are chemi-
diffusion occurs down a concentration gradient; thus, it cally operated and respond to speci c receptor-bound
does not require input of metabolic energy. Unlike simple ligands, such as the neurotransmitter acetylcholine; and
diffusion, however, facilitated diffusion requires a trans- m echanically gated channels, which open or close in
port protein. Some substances, such as glucose, can- response to such mechanical stimulations as vibrations,
not pass unassisted through the cell membrane because tissue stretching, or pressure.
they are not lipid soluble or they are too large to pass
through the membranes pores. These substances com- Move m e nt o f Wate r Acro s s the Ce ll Me m brane .
bine with special transport proteins at the membranes Water molecules move through adjacent phospholipid

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C H A P T E R 1 Cell Structure and Function 15

60 mV Ion 45 mV Ions

Liga nd Ion Liga nd Ions

FIG U RE 1-1 2 . Ga te d io n ch a n n e ls th a t o p e n in Re ce ptor Re ce ptor

re s p o n s e to s p e ci c s tim u li. (A) Vo lta g e -ga te d
ch a n n e ls a re co n tro lle d b y a ch a n g e in th e
m e m b ra n e p o te n tia l. (B) Liga n d -ga te d ch a n n e ls
a re co n tro lle d b y b in d in g o f a liga n d to a
re ce p to r.

molecules in the cell membrane by osmosis without membrane pump, the osmotically active sodium parti-
actually dissolving in the region occupied by the fatty cles would accumulate in the cell, causing cellular swell-
acid side of the chains. O smosis is regulated by the con- ing because of an accompanying in ux of water.
centration of nondiffusible particles on either side of
the membrane, with water moving from the side with Se co ndary Active Trans po rt. Secondary active trans-
the lower concentration of particles to the side with the port mechanisms harness the energy derived from the pri-
higher concentration. The cell membranes of most cells mary active transport of one substance, usually sodium,
also contain transmembrane proteins, called aquapo- for the cotransport of a second substance. For example,
rins, that function as water channels. Aquaporins are when sodium ions are actively transported out of a cell by
especially abundant in cells that must transport water primary active transport, a large concentration gradient
at particularly high rates, such as certain cells of the develops (i.e., high concentration on the outside and low
kidney. on the inside). This concentration gradient represents a
large storehouse of energy because sodium ions are always
Active Trans po rt attempting to diffuse into the cell. Similar to facilitated
diffusion, secondary transport uses membrane transport
The process of diffusion describes particle movement proteins. These proteins have two binding sites: one for
from an area of higher concentration to one of lower sodium and the other for the substance undergoing sec-
concentration, resulting in an equal distribution of per- ondary transport. Secondary active transport systems
meable substances across the cell membrane. Sometimes, are classi ed into two groups: cotransport, or symport
however, different concentrations of a substance are systems, in which sodium and the solute are transported
needed in the intracellular and extracellular uids. For in the same direction, and countertransport, or antiport
example, to function, a cell requires a higher intracel- systems, in which sodium and the solute are transported
lular concentration of potassium ions than is present in in the opposite directions. An example of cotransport
the extracellular uid, while maintaining a much lower occurs in the intestine, where the absorption of glucose
concentration of sodium ions than the extracellular and amino acids is coupled with sodium transport.
uid. In these situations, energy is required to pump the
ions uphill or against their concentration gradient. Ve s icular Trans po rt
When cells use energy to move ions against an electrical
or chemical gradient, the process is called active trans- Vesicular transport is a mechanism in which materials
port. Two types of active transport systems exist: pri- are transported in membrane-bound vesicles. There are
mary active transport and secondary active transport. two types of vesicular transport: endocytosis, in which
materials are moved into a cell in a vesicle formed from
Prim ary Active Trans po rt. Among the substances that the cell membrane, and ex ocytosis, in which materials
are transported by primary active transport are sodium, are moved out of a cell by fusion of a vesicle with the
potassium, calcium, and hydrogen ions. The active cell membrane.
transport system studied in the greatest detail is the Endocytosis is the process by which cells engulf mate-
sodium/potassium (N a +/K+)-adenosine triphosphatase rials from their surroundings. In the process, the mate-
(ATPase) membrane pump. The N a +/K+ATPase mem- rial is progressively enclosed in small portions of the cell
brane pump moves sodium from inside the cell to the membrane, which rst invaginates (folds inward) and
extracellular region, where its concentration is approxi- then pinches off to become an endocytotic vesicle. If the
mately 14 times greater than inside; the pump also vesicle is small (>150 nm in diameter), the process is
returns potassium to the inside, where its concentration called pinocytosis, and the vesicle is called a pinocytotic
is approximately 35 times greater than it is outside the vesicle; if the vesicle is large (>250 nm in diameter), the
cell. If it were not for the activity of the N a +/K+ATPase process is called phagocytosis, and the vesicle is called

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16 U N I T 1 Cell and Tissue Function

a phagosom e. The process of pinocytosis, which means cells in the body. Because these potentials occur at the
cell drinking, is important in the transport of pro- level of the cell membrane, they are called m em brane
teins and strong solutions of electrolytes. Phagocytosis, potentials. In excitable tissues, such as nerve or muscle
which means cell eating, involves the engulfment and cells, changes in the membrane potential are necessary
subsequent killing or degradation of microorganisms for generation and conduction of nerve impulses and
and other particulate matter. Certain cells, such as mac- muscle contraction. In other types of cells, such as glan-
rophages and neutrophils, are adept at engul ng and dular cells, changes in the membrane potential contrib-
disposing of invading organisms, damaged cells, and ute to hormone secretion and other functions.
unneeded extracellular constituents. Electrical potentials describe the ability of separated
Ex ocytosis is the mechanism for the secretion of electrical charges of opposite polarity (+ and ) to do
intracellular substances into the extracellular spaces. It work. In regard to cells, the oppositely charged particles
may be considered a reverse of endocytosis in that the are ions, and the barrier that separates them is the cell
membrane of the secretory granule fuses with the cell membrane. Electrical potentials are measured in volts
membrane and allows the contents of the granule to be (V) or units of electromotive force (EM F). Voltage is
released into the extracellular uid. Exocytosis is impor- always measured with respect to two points in a system.
tant in removing cellular debris and releasing substances, For example, the voltage in a car battery (6 or 12 V)
such as hormones and cytokines, synthesized in the cell. is the potential difference between the two battery ter-
R eceptor-m ediated endocytosis involves the binding minals. In a cell it is the potential difference between
of substances to a receptor on the cell surface. M any the inside and outside of the cell membrane. Because
of these receptor proteins are concentrated in clathrin- the total amount of charge that can be separated by a
coated pits, which are speci c areas of the cell where the biologic membrane is small, the potential differences are
membrane is lined on its cytoplasmic side by a periph- small and are therefore measured in millivolts (mV), or
eral protein called clathrin. The interaction between 1/1000 of a volt.
the proteins in the receptorligand complex causes the There are two main factors that alter membrane
membrane to invaginate. The edges of the membrane potentials: the difference in the concentration of ions on
around the clathrin-coated pit then fuse, and a por- the inside and outside of the membrane and the perme-
tion of the membrane pinches off as an endocytic ves- ability of the membrane to these ions. Extracellular and
icle. Almost immediately after it is formed, the vesicle intracellular uids are electrolyte solutions containing
loses its clathrin coat and becomes fused with an early approximately 150 to 160 mmol/L of positively charged
endosome in a manner similar to that involved in non ions and an equal concentration of negatively charged
receptor-mediated endocytosis. The uptake of choles- ions. The diffusion of these current-carrying ions is
terol transported in the blood as low-density lipoprotein responsible for generating and conducting membrane
(LDL) relies on receptor-mediated removal associated potentials. A diffusion potential describes the voltage
with clathrin-coated pits. This pathway for cholesterol generated by ions that diffuse across the cell membrane.
removal is disrupted in persons who inherit defective An equilibrium potential is one in which there is no
genes for encoding LDL receptors (see Chapter 18). net movement of a particular ion across a membrane
In addition to clathrin-coated pits and vesicles, there because the diffusion potential and electrical forces gen-
are a number of other mechanisms by which cells can form erated by the movement of the ion are exactly balanced.
endocytotic vesicles. O ne of these pathways involves the The magnitude of the equilibrium potential, also known
formation of small invaginations or little cavities in as the N ernst potential, is determined by the ratio of the
the cell membrane, called caveolae, that extend inward, concentration of a speci c ion on the two sides of the
indenting the cell membrane and the cytoplasm. These membrane. The greater the ratio, the greater the ten-
cavities may pinch off and form free vesicles within dency for the ion to diffuse in one direction, and there-
the cytoplasm. Caveolae are considered to be sites for fore the greater the electrical forces required to prevent
uptake of material into the cell, for expulsion of material further diffusion. The N ernst equation (described in the
from the cell, and for addition or removal of cell mem- gure on Understanding M embrane Potentials) can be
brane components. In smooth muscle, caveolae project used to calculate the equilibrium potential for any uni-
into the cytoplasm and, analogous to the T tubules in valent ion at a given concentration difference, assum-
striated muscle, play an important role in regulating ing that membrane is permeable to the ion. When using
intracellular calcium concentration and smooth muscle the equation, it is generally assumed that the electrical
tone. In addition to transport, caveolae are involved in potential of the extracellular uid outside the membrane
a number of other functions such as signal transduction remains at zero and the potential being calculated is
and may be involved in the pathogenesis of a number of the electrical potential inside the membrane. It is also
diseases, including muscular dystrophy. assumed that the sign of the potential is negative () if
a positively charged ion diffuses from the inside to the
outside of the membrane and positive (+) if a positively
G e n e r a t io n o f M e m b r a n e P o t e n t ia ls charged ion diffuses from the outside to the inside of the
Living organisms have electrical properties in which The resting m em brane potential represents the period
current ow involves the movement of ions in water. of time when excitable cells, such as nerve bers, are not
Electrical potentials exist across the membranes of most transmitting signals. Because resting cell membranes are

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C H A P T E R 1 Cell Structure and Function 17

more permeable to potassium than sodium, the resting

membrane re ects the diffusion of potassium ions. The Ele ctrica l p o te n tia ls , w h ich a re m e a s u re d
N a +/K+-ATPase membrane pump, which removes three in vo lts , d e s crib e th e a b ility o f s e p a ra te d
N a + from inside the cell while returning two K+ to the e le ctrica l ch a rg e s o f o p p o s ite p o la rity
inside, assists in maintaining the resting membrane (+ a n d ) to d o w o rk. In re g a rd to ce lls , th e
potential. During an action potential, the cell membrane o p p o s ite ly ch a rg e d p a rticle s a re io n s , a n d
becomes more permeable to sodium, causing its polarity th e b a rrie r th a t s e p a ra te s th e m is th e ce ll
to change so that it is positive on the inside and negative m e m b ra n e . Th e re a re tw o m a in fa cto rs th a t
on the outside (discussed in Chapter 34).
a lte r m e m b ra n e p o te n tia ls a n d e xcita b ility:
th e d iffe re n ce in co n ce n tra tio n o f io n s o n
th e in s id e a n d o u ts id e o f th e m e m b ra n e a n d
S U M M A R Y C O N C EP TS th e p e rm e a b ility o f th e m e m b ra n e to th e s e
io n s . An e q u ilib riu m p o te n tia l is o n e in w h ich
th e re is n o n e t m o ve m e n t o f a p a rticu la r io n
Ce lls co m m u n ica te w ith e a ch o th e r b y ch e m ica l a cro s s a m e m b ra n e b e ca u s e th e d iffu s io n a n d
m e s s e n g e r s ys te m s . Ch e m ica l m e s s e n g e rs e le ctrica l fo rce s g e n e ra te d b y th e m o ve m e n t
b in d to re ce p to rs o n o r n e a r th e ce ll s u rfa ce . o f th e io n s a re e xa ctly b a la n ce d . Th e re s tin g
Th e re a re th re e cla s s e s o f ce ll s u rfa ce re ce p to r m e m b ra n e p o te n tia l ( o u ts id e a n d + in s id e ) is
p ro te in s : G p ro te in -lin ke d , e n zym e -lin ke d , a n d e s s e n tia lly a p o ta s s iu m e q u ilib riu m p o te n tia l
ch a n n e l-lin ke d . G p ro te in lin ke d re ce p to rs re ly th a t re s u lts fro m th e s e le ctive p e rm e a b ility o f
o n a cla s s o f m o le cu le s ca lle d G p ro te in s th a t th e m e m b ra n e to th e p o ta s s iu m io n a n d th e
fu n ctio n a s a n o n o ff s w itch to co nve rt e xte rn a l la rg e d iffe re n ce in p o ta s s iu m co n ce n tra tio n th a t
s ig n a ls ( rs t m e s s e n g e rs ) in to in te rn a l s ig n a ls e xis ts b e tw e e n th e in s id e a n d th e o u ts id e o f
(s e co n d m e s s e n g e rs ). En zym e -lin ke d re ce p to rs th e m e m b ra n e . Du rin g a n a ctio n p o te n tia l, th e
h a ve in trin s ic e n zym e a ctivity o r re ly o n e n zym e s ce ll m e m b ra n e b e co m e s h ig h ly p e rm e a b le to
th a t a re clo s e ly a s s o cia te d w ith th e re ce p to r th e y s o d iu m , ca u s in g it to d e p o la rize a n d re ve rs e its
a ctiva te . On e typ e o f e n zym e -lin ke d re ce p to r is p o la rity ( in s id e a n d + o u ts id e ).
w id e ly u s e d in h o rm o n a l co n tro l o f ce ll fu n ctio n
a n d invo lve s th e a ctiva tio n o f th e e n zym e
a d e nylyl cycla s e , w h ich ca ta lyze s th e fo rm a tio n
o f cAMP, a s e co n d m e s s e n g e r th a t h a s m u ltip le
e ffe cts in s id e th e ce ll. Activa tio n o f io n ch a n n e l
lin ke d re ce p to rs (e .g ., b y n e u ro tra n s m itte rs ) m a y Tis s u e s
trig g e r s ig n a lin g to tra n s ie n tly o p e n o r clo s e io n
ch a n n e ls fo rm e d b y in te g ra l p ro te in s in th e ce ll. In the preceding sections, we discussed the individual
cell, its metabolic processes, and mechanisms of signal-
S u b s ta n ce s th a t e n te r o r le a ve th e ce ll m u s t
ing and communication. Although cells have similari-
cro s s th e ce ll m e m b ra n e . Diffu sio n is a p ro ce s s
ties, their structures and functions vary according to the
b y w hich su bsta n ce s s uch a s ion s m ove fro m speci c needs of the body. For example, muscle cells are
a re as of g rea te r co n cen tra tio n to area s o f les se r specialized to perform different functions from skin cells
co n ce n tra tio n u n til re a ch in g a u n ifo rm d is trib u tio n . or nerve cells. Groups of cells that are closely associated
Fa cilita te d diffusion is a pa ss ive proce ss , in w hich in structure and have common or similar functions are
m olecu le s tha t can not no rm a lly pas s throug h called tissues. Four categories of tissue exist: (1) epithe-
the ce lls m e m bra n e s do so with th e a ss is ta n ce lial, (2) connective, (3) muscle, and (4) nervous. These
o f a ca rrie r m ole cu le . Active tra ns port re qu ire s tissues do not exist in isolated units but in association
the ce ll to e xp e nd e ne rgy in m oving ions a ga in st with each other and in variable proportions, forming
a co n cen tra tio n g ra dien t. Th e Na +/K+-ATPa s e different structures and organs of the body. This sec-
tion of the chapter provides a brief overview of the
m e m b ra n e p u m p is th e b e s t-kn o w n typ e o f a ctive
cells in each of the four tissue types, the structures that
tra n s p o rt. Ve s icu la r tra n s p o rt is a m ech a n ism in
hold these cells together, and the extracellular matrix in
w h ich a ce ll e n clo s e s e xtra ce llu la r m a te ria l in a which they live.
m e m b ra n e -b o u n d ve s icle . Th e re a re tw o typ e s o f
ve s icu la r tra n s p o rt: e nd o cyto s is, in wh ich m a te ria ls
a re b ro u g h t in to th e ce ll b y inva g in a tio n o f th e Em b ryo n ic O r ig in o f Tis s u e Ty p e s
ce ll m e m bra ne to form a ve sicle , a n d e xo cyto s is ,
After conception, the fertilized ovum undergoes a series
in w hich m a te ria ls a re e xporte d from the ce ll b y of divisions, ultimately forming different cell types that
fu s io n o f a ve s icle w ith th e ce ll m e m b ra n e . comprise the various tissues of the body. The forma-
tion of different, more specialized types of cells and
(tex t continues on page 20)

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18 U N I T 1 Cell and Tissue Function

U N D E R S TA N D IN G Me m b ra ne Po te ntia ls
Electrochem ical potentials are present across the m em branes of virtually all
cells in the body. Som e cells, such as nerve and m uscle cells, are capable
of generating rapidly changing electrical im pulses and transm itting these
im pulses along their m em branes. Generation of m em brane potentials relies
on (1) diffusion of current-carrying ions, (2) developm ent of an electrochem ical
equilibrium , and (3) establishm ent of a resting m em brane potential and
triggering an action potential.

1 Volts

Diffu s io n p o t e n t ia ls . A diffusion 0
potential is a potential difference
generated across a membrane when
a current-carrying ion, such as the
potassium (K+) ion, diffuses down
its concentration gradient. Two
conditions are necessary for this to Outs ide ce ll
occur: (1) the membrane must be
selectively permeable to a particular
ion, and (2) the concentration of the
diffusible ion must be greater on one
side of the membrane than the other. Ins ide ce ll
The magnitude of the diffusion
potential, measured in millivolts
(mV), depends on the size of the con-
centration gradient. The sign (+ or )
or polarity of the potential depends K+pe rme a ble
on the diffusing ion. It is negative on me mbra ne
the inside when a positively charged
ion such as K+ diffuses from the K+ K+
inside to the outside of the mem- K+ K+
brane, carrying its charge with it.
Conce ntra tion gra die nt for K+

Ele ctrica l (ionic)

2 pote ntia l
Eq u ilib riu m p o t e n t ia ls . An equi-
librium potential is the membrane Equilibrium
potential that exactly balances and pote ntia l
opposes the net diffusion of an ion
down its concentration gradient. As a
cation diffuses down its concentration Diffus ion (che mica l)
gradient, it carries its positive charge gra die nt
across the membrane, thereby gener-
ating an electrical force that will even-
Ne rn s t e q u a tio n
tually retard and stop its diffusion. EMF (mV) = 61 log 10 (ion conce ntra tion ins ide /
An electrochemical equilibrium is one ion conce ntra tion outs ide )
in which the chemical forces driving
diffusion and the repelling electrical
forces are exactly balanced so that no
further diffusion occurs. The equilib-
rium potential (EMF, electromotive
force) can be calculated by inserting
the inside and outside ion concentra-
tions into the Nernst Equation.

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C H A P T E R 1 Cell Structure and Function 19

2 K+
3 K+
Re s t in g m e m b r a n e p o t e n t ia l
(RM P ). The RM P, which is neces-
sary for electrical excitability, is pres- Na +/K+
ent when the cell is not transmitting
impulses. Because the resting mem-
brane is permeable to K+, it is essen- A- K+
tially an K+ equilibrium potential. 3 Na + Conce ntra tion
This can be explained in terms of gra die nt for K+
the large K+ concentration gradient
(e.g., 140 mEq/L inside and 4 mEq/L
outside), which causes the positively
charged K+ to diffuse outward, leav-
ing the nondiffusible, negatively
Outs ide ce ll
charged intracellular anions (A)
behind. This causes the membrane
to become polarized, with negative
charges aligned along the inside and
positive charges along the outside. Ins ide ce ll
The N a +/K+ membrane pump, which
removes three N a + from inside while
returning only two K+ to the inside,
contributes to the maintenance of
the RM P.

Na + Na + Na +
4 Na + Na +
Ac t io n p o t e n t ia ls . Action poten-
tials involve rapid changes in the
membrane potential. Each action
potential begins with a sudden
change from the negative RM P to a
positive threshold potential, causing
an opening of the membrane chan-
nels for N a + (or other ions of the
action potential). O pening of the Trigge ring eve nt ope ning
N a + channels allows large amounts Na + cha nne ls
of the positively charged N a + ions
to diffuse to the interior of the cell,
causing the membrane potential to Outs ide ce ll
undergo depolarization or a rapid
change to positive on the inside and
negative on the outside. This is rap-
idly followed by closing of N a + chan- Ins ide ce ll
nels and opening of the K+ channels,
which leads to a rapid ef ux of K+
from the cell and reestablishment of
the RM P.

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20 U N I T 1 Cell and Tissue Function

TA BLE 1 - 1 Clas s i catio n o f Tis s ue Type s

Tis s u e Ty p e Lo c a t io n

Ep it h e lia l Tis s u e
Co ve rin g a n d lin in g o f b o d y s u rfa ce s
S im p le e p ith e liu m
Squam ous Lin in g o f b lo o d ve s s e ls , b o d y ca vitie s , a lve o li o f lu n g s
Cu b o id a l Co lle ctin g tu b u le s o f kid n e y; cove rin g o f ova rie s
Co lu m n a r Lin in g o f in te s tin e a n d ga llb la d d e r
S tra ti e d e p ith e liu m
S q u a m o u s ke ra tin ize d S kin
S q u a m o u s n o n ke ra tin ize d Mu co u s m e m b ra n e s o f m o u th , e s o p h a g u s , a n d va g in a
Cu b o id a l Du cts o f s w e a t g la n d s
Co lu m n a r La rg e d u cts o f s a liva ry a n d m a m m a ry g la n d s ; a ls o fo u n d in co n ju n ctiva
Tra n s itio n a l Bla d d e r, u re te rs , re n a l p e lvis
Ps e u d o s tra ti e d Tra ch e a l a n d re s p ira to ry p a s s a g e s
Gla n d u la r
En d o crin e Pitu ita ry g la n d , thyro id g la n d , a d re n a l a n d o th e r g la n d s
Exo crin e S w e a t g la n d s a n d g la n d s in ga s tro in te s tin a l tra ct
Ne u ro e p ith e liu m Olfa cto ry m u co s a , re tin a , to n g u e
Re p ro d u ctive e p ith e liu m Se m in ife ro u s tu b u le s o f te s tis ; co rtica l p o rtio n o f ova ry

Co n n e ct ive Tis s u e
Em b ryo n ic co n n e ctive tis s u e
Me s e n chym a l Em b ryo n ic m e s o d e rm
Mu co u s Um b ilica l co rd (Wh a rto n je lly)
Ad u lt co n n e ctive tis s u e
Lo o s e o r a re o la r S u b cu ta n e o u s a re a s
De n s e re g u la r Te n d o n s a n d liga m e n ts
De n s e irre g u la r De rm is o f s kin
Ad ip o s e Fa t p a d s , s u b cu ta n e o u s la ye rs
Re ticu la r Fra m e w o rk o f lym p h o id o rga n s , b o n e m a rro w, live r
S p e cia lize d co n n e ctive tis s u e
Bo n e Lo n g b o n e s , a t b o n e s
Ca rtila g e Tra ch e a l rin g s , e xte rn a l e a r, a rticu la r s u rfa ce s
He m a to p o ie tic Blo o d ce lls , m ye lo id tis s u e (b o n e m a rro w )

Mu s cle Tis s u e
S ke le ta l S ke le ta l m u s cle s
Ca rd ia c He a rt m u s cle s
S m o o th Ga s tro in te s tin a l tra ct, b lo o d ve s s e ls , b ro n ch i, b la d d e r, a n d o th e rs

Ne rvo u s Tis s u e
Ne u ro n s Ce n tra l a n d p e rip h e ra l n e u ro n s a n d n e rve b e rs
S u p p o rtin g ce lls Glia l a n d e p e n d ym a l ce lls in ce n tra l n e rvo u s s ys te m ; Sch wa n n a n d s a te llite ce lls
in p e rip h e ra l n e rvo u s s ys te m

(tex t continued from page 17)

tissues is called cell differentiation, a process that is Ep it h e lia l Tis s u e
controlled by mechanisms that switch genes on and off
(see Chapter 4). Epithelial tissue forms sheets that cover the bodys outer
All of the approximately 200 different cells of the surface, line the internal surfaces, and form glandular tis-
body can be classi ed into the four basic or primary tis- sue. Underneath all types of epithelial tissue is a brous
sue types: epithelial, connective, muscle, and nervous extracellular layer, called the basem ent m em brane,
(Table 1-1). These basic tissue types are often described which serves to attach the epithelial cells to adjacent
by their embryonic origin. The embryo is essentially a connective tissue and may serve other functions, such
three-layered tubular structure (Fig. 1-13). The outer as providing a barrier against cancer cell invasion and
layer of the tube is called the ectoderm ; the middle layer, contributing to the ltration function of the glomerulus.
the m esoderm ; and the inner layer, the endoderm . All of The cells that make up epithelium have three general
the mature tissue types originate from these three cel- characteristics: (1) they have three distinct surfaces: a
lular layers. Epithelium has its origin in all three embry- free surface or apical surface, a lateral surface, and a
onic layers, connective tissue and muscle develop mainly basal surface; (2) they are closely apposed and joined
from the mesoderm, and nervous tissue develops from by cell-to-cell adhesion molecules, which form special-
the ectoderm. ized cell junctions; and (3) their basal surface is attached

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C H A P T E R 1 Cell Structure and Function 21

Ne ura l cre s t (cra nia l a nd s e ns ory ga nglia a nd Ne ura l tube (ce ntra l
ne rve s , a dre na l me dulla , me la nocyte s a nd ne rvous s ys te m,
S chwa nn ce lls ) re tina , pos te rior
pituita ry gla nd)

S omite s (s ke le ta l
a nd trunk mus cle s Dors a l a orta
a nd conne ctive
tis s ue )
Vis ce ra l s e rous
me mbra ne s
Uroge nita l ridge (pe ritone um, ple ura ,
(ge nita lia , gona ds , pe rica rdium)
urina ry s tructure s )
S oma tic s e rous
Do rs a l me mbra ne
m e s e n te ry (pe ritone um)

La te ra l a nd ve ntra l S urfa ce e ctode rm

P e rito n e a l S u rfa c e (e pide rmis , ha ir, na ils ,
a bdomina l wa lls c a vity
(a bdomina l mus cle s cuta ne ous a nd
a nd conne ctive tis s ue ) ma mma ry gla nds )
Epithe lium of
ga s trointe s tina l a nd
re s pira tory tra cts ,
thyroid, a nd pa ra thyroid
gla nds , tons ils a nd
pha ryngotympa nic tube

Endode rm

Me s ode rm
FIG U RE 1-1 3 . Cro s s -s e ctio n o f h u m a n e m b ryo
illu s tra tin g th e d e ve lo p m e n t o f th e s o m a tic Ectode rm
a n d vis ce ra l s tru ctu re s .

to the underlying basement membrane (Fig. 1-14). The membranes that line the pleural, pericardial, and perito-
characteristics and geometric arrangement of the cells neal cavities and covers the organs of these cavities. A
in the epithelium contribute to their function. In an epi- sim ple cuboidal epithelium is found on the surface of the
thelium formed from a single layer of epithelial cells, the ovary and in the thyroid. Sim ple colum nar epithelium
free or apical surface is directed toward the exterior sur- lines the intestine. O ne form of a simple columnar epi-
face or lumen of an enclosed cavity or tube, the lateral thelium has hair-like projections called cilia, often with
surface communicates with adjacent cells and is charac- specialized mucus-secreting cells called goblet cells. This
terized by specialized attachment areas, and the basal form of simple columnar epithelium lines the airways of
surface rests on the basement membrane anchoring the the respiratory tract.
cell to the surrounding connective tissue.
Epithelial tissues are classi ed according to the shape S trati e d and Ps e udo s trati e d Epithe lium
of the cells and the number of layers that are present:
Strati ed epithelium contains more than one layer of
simple, strati ed, and pseudostrati ed. Glandular epi-
cells, with only the deepest layer resting on the basement
thelial tissue is formed by cells specialized to produce
membrane. It is designed to protect the body surface.
a uid secretion. The terms squam ous (thin and at),
Strati ed squam ous k eratinized epithelium makes up the
cuboidal (cube shaped), and colum nar (resembling a
epidermis of the skin. Keratin is a tough, brous protein
column) refer to the cells shape (Fig. 1-15).
that polymerizes to form intermediate laments that are
abundant in the outer cells of skin. A strati ed squamous
S im ple Epithe lium
keratinized epithelium is made up of many layers. The
Simple epithelium contains a single layer of cells, all of layers closest to the underlying tissues are cuboidal or
which rest on the basement membrane. Simple squamous columnar. The cells become more irregular and thinner
epithelium is adapted for ltration; it is found lining the as they move closer to the surface. Surface cells become
blood vessels, lymph nodes, and alveoli of the lungs. The totally lled with keratin and die, are sloughed off, and
single layer of squamous epithelium lining the heart and then replaced by the deeper cells. A strati ed squamous
blood vessels is known as the endothelium . A similar nonkeratinized epithelium is found on moist surfaces
type of layer, called the m esothelium , forms the serous such as the mouth and tongue. Strati ed cuboidal and

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22 U N I T 1 Cell and Tissue Function

Ce ll Microvilli S imple s qua mous

Apica l s urfa ce

Epithe lia l ce lls

S imple cuboida l

Ba s e me nt me mbra ne
Conne ctive tis s ue
S imple columna r
Ne rve fibe r
Blood ve s s e l

FIG U RE 1-1 4 . Typ ica l a rra n g e m e n t o f e p ith e lia l ce lls in re la tio n

to u n d e rlyin g tis s u e s a n d b lo o d s u p p ly. Ep ith e lia l tis s u e h a s n o
b lo o d s u p p ly o f its o w n b u t re lie s o n th e b lo o d ve s s e ls in th e
u n d e rlyin g co n n e ctive tis s u e fo r n u tritio n (N) a n d e lim in a tio n
o f wa s te s (W).
P s e udos tra tifie d columna r
columnar epithelia are found in the ducts of salivary cilia te d
glands and the larger ducts of the mammary glands. In
smokers, the normal columnar ciliated epithelial cells of
the trachea and bronchi are often replaced with strati-
ed squamous epithelial cells that are better able to with-
stand the irritating effects of cigarette smoke.
Pseudostrati ed epithelium is a type of epithelium in
which all of the cells are in contact with the underly-
ing intercellular matrix, but some do not extend to the
Tra ns itiona l
surface. A pseudostrati ed ciliated columnar epithelium
with goblet cells forms the lining of most of the upper
respiratory tract. All of the tall cells reaching the sur-
face of this type of epithelium are either ciliated cells
or mucus-producing goblet cells. The basal cells that do
not reach the surface serve as stem cells for ciliated and
goblet cells.
Transitional epithelium is a strati ed epithelium
characterized by cells that can change shape and become
thinner when the tissue is stretched. Such tissue can be S tra tifie d s qua mous
stretched without pulling the super cial cells apart.
Transitional epithelium is well adapted for the lining of
organs that are constantly changing their volume, such
as the urinary bladder.

Glandular Epithe lium

Glandular epithelial tissue is formed by cells special-
ized to produce a uid secretion. This process is usually FIG U RE 1-1 5 . Re p re s e n ta tio n o f th e va rio u s e p ith e lia l tis s u e
accompanied by the intracellular synthesis of macromol- typ e s .
ecules. The chemical nature of these macromolecules is
variable. The macromolecules typically are stored in the
cells in small membrane-bound vesicles called secretory glands), and complexes of carbohydrates and proteins
granules. For example, glandular epithelia can synthe- (e.g., saliva). Less common are secretions that require
size, store, and secrete proteins (e.g., insulin), lipids (e.g., minimal synthetic activity, such as those produced by
adrenocortical hormones, secretions of the sebaceous the sweat glands.

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C H A P T E R 1 Cell Structure and Function 23

All glandular cells arise from surface epithelia by Ground

means of cell proliferation and invasion of the underlying s ubs ta nce Colla ge n fibe rs
Ma s t ce ll Ca pilla ry
connective tissue. Epithelial glands can be divided into Ma cropha ge
two groups: exocrine and endocrine glands. Exocrine
glands, such as the sweat glands and lactating mam-
mary glands, retain their connection with the surface
epithelium from which they originated. This connection
takes the form of epithelium-lined tubular ducts through
which the secretions pass to reach the surface. Endocrine
glands are epithelial structures that have had their con-
nection with the surface obliterated during development.
These glands are ductless and produce secretions (i.e.,
hormones) that move directly into the bloodstream.

Epithe lial Ce ll Re ne w al
Cells making up the epithelial tissues generally exhibit
a high rate of turnover, which is related to their loca-
tion and function. The rate of cell turnover is character-
istic of speci c epithelium. For example, the epithelial
cells of the small intestine are renewed every 4 to 6 days
by regenerative cells in the lower portion of the intesti-
nal glands (crypts). Similarly, the cells of the strati ed Adipocyte P la s ma ce ll Fibrobla s t White Ela s tic fibe r
squamous epithelium of the skin are constantly being blood ce ll
renewed at the basal layer by cell division. FIG U RE 1-1 6 . Dia g ram m a tic re pre senta tion o f ce lls th at m a y
b e seen in lo ose con nective tissue. Th e cells lie in an intercellular
m atrix that is bathed in tissue uid that originates in the capillaries.
C o n n e c t ive Tis s u e
Connective or supportive tissue is the most abundant by which these tissues are nourished. Loose connec-
tissue in the body. As its name suggests, it connects and tive tissue is characterized by an abundance of ground
binds or supports the various tissues. Connective tis- substance and tissue uid housing the xed connective
sue is unique in that its cells produce the extracellular tissue cells: broblasts, mast cells, adipose or fat cells,
matrix that supports and holds tissues together. The macrophages, and leukocytes. Fibroblasts are the most
proximity of the extracellular matrix to blood vessels abundant of these cells. They produce all three ber
allows it to function as an exchange medium through typescollagen, elastic, and reticular bersfound in
which nutrients and metabolic wastes pass. loose connective tissue, and synthesize the ground sub-
The functions of the various connective tissues are stance that lls the intercellular tissue spaces.
re ected by the types of cells and bers present in the
tissue and the characteristics of the extracellular matrix Adipo s e Tis s ue
(Fig. 1-16). The capsules that surround organs of the
body are composed of connective tissue. Bone, adipose Adipose tissue is a special form of connective tissue
tissue, and cartilage are specialized types of connective in which adipocytes predominate. Adipocytes do not
tissue that function to support the soft tissues of the body generate an extracellular matrix but maintain a large
and store fat. O ne type of cell, the broblast, is respon- intracellular space. These cells store large quantities of
sible for synthesis of collagen, elastic, reticular bers, and triglycerides and are the largest repository of energy in
ground substance of the extracellular matrix. O ther cells, the body. Adipose tissue helps ll spaces between tissues
such as lymphocytes, plasma cells, macrophages, and and to keep organs in place. The subcutaneous fat helps
eosinophils, are associated with body defense systems. to shape the body. Because fat is a poor conductor of
Adult connective tissue can be divided into two types: heat, adipose tissue serves as thermal insulation for the
connective tissue proper, which is the focus of the dis- body. Adipose tissue exists in two forms: unilocular and
cussion in this chapter, and specialized connective tissue multilocular. Unilocular (white) adipose tissue is com-
(cartilage, bone, and blood cells), which is discussed in posed of cells in which the fat is contained in a single,
other chapters. There are four recognized types of con- large droplet in the cytoplasm. M ultilocular (brown)
nective tissue proper: loose (areolar), adipose, reticular, adipose tissue is composed of cells that contain multiple
and dense connective tissue. droplets of fat and numerous mitochondria.

Lo o s e Co nne ctive Tis s ue Re ticular and De ns e Co nne ctive Tis s ue

Loose connective tissue, also known as areolar tissue, is Reticular and dense connective tissue is characterized by a
soft and pliable. It lls spaces between muscle sheaths, network of bers interspersed with macrophages and bro-
forms a layer that encases blood and lymphatic vessels, blasts that synthesize collagen bers. R eticular bers pro-
and provides support for epithelial tissues and the means vide the framework for capillaries, nerves, and muscle

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24 U N I T 1 Cell and Tissue Function

cells. They also constitute the main supporting elements mechanisms, they have many similarities. In the follow-
for the blood-forming tissues and the liver. ing section, the structural properties of skeletal muscle
Dense connective tissue exists in two forms: dense irreg- are presented as the prototype of striated muscle tissue.
ular and dense regular. Dense irregular connective tissue Smooth muscle and the ways in which it differs from
consists of the same components found in loose connec- skeletal muscle are also discussed. Cardiac muscle is
tive tissue but exhibits a predominance of collagen bers described in Chapter 17.
and fewer cells. This type of tissue can be found in the
dermis of the skin (i.e., reticular layer), the brous capsules S ke le tal Mus cle
of many organs, and the brous sheaths of cartilage (i.e.,
Skeletal muscle is the most abundant tissue in the body,
perichondrium) and bone (i.e., periosteum). It also forms
accounting for 40% to 45% of the total body weight.
the fascia that invests muscles and organs. Dense regular
Most skeletal muscles are attached to bones, and their con-
connective tissues are rich in collagen bers and form the
tractions are responsible for movements of the skeleton.
tendons and aponeuroses that join muscles to bone or
other muscles and the ligaments that join bone to bone.
S ke le tal Mus cle S tructure . Skeletal muscle bers are
packaged into skeletal muscles that attach to and cover
the body skeleton. Each skeletal muscle is a discrete
organ made up of hundreds or thousands of muscle
M u s c le Tis s u e bers. Although muscle bers predominate, substantial
Muscle tissue, whose primary function is contraction, is amounts of connective tissue, blood vessels, and nerve
responsible for movement of the body and its parts and for bers are present. In an intact muscle, several different
changes in the size and shape of internal organs. M uscle layers of connective tissue hold the individual muscle
tissue contains two types of bers that are responsible for bers together. Skeletal muscles such as the biceps
contraction: thin actin and thick myosin laments. brachii are surrounded by a dense irregular connec-
There are three types of muscle tissues: skeletal, car- tive tissue covering called the epim ysium (Fig. 1-17A).
diac, and smooth. Sk eletal and cardiac m uscles are stri- Each muscle is subdivided into smaller bundles called
ated muscles, in which the actin and myosin laments fascicles, which are surrounded by a connective tissue
are arranged in large parallel arrays in bundles, giving covering called the perim ysium . The number of fascicles
the muscle bers a striped or striated appearance when and their size vary among muscles. Fascicles consist of
observed with a microscope. Sm ooth m uscle lacks stria- many elongated structures called m uscle bers, each
tions and is found in the iris of the eye; the walls of of which is surrounded by connective tissue called the
blood vessels; hollow organs, such as the stomach and endom ysium .
urinary bladder; and hollow tubes, such as the ureters Skeletal muscles are syncytial or multinucleated struc-
and common bile duct that connect internal organs. tures, meaning there are no true cell boundaries within a
Although the three types of muscle tissues differ sig- skeletal muscle ber. The cytoplasm or sarcoplasm of the
ni cantly in structure, contractile properties, and control muscle ber is contained within the sarcolemma, which

Bone S ke le ta l mus cle s urrounde d

by e pimys ium

Fa s cicle s urrounde d by
pe rimys ium
Te ndon Mus cle fibe r (ce ll)
A s urrounde d by
Blood ve s s e l e ndomys ium

S a rcome re
M line Myofibrils
conta ine d
in mus cle fibe r
FIG U RE 1-1 7. (A) Co n n e ctive tis s u e
T tubule s co m p o n e n ts o f a s ke le ta l m u s cle . (B)
H zone I ba nd S tria tio n s o f th e m yo b ril s h o w in g th e
Z line ove rla p o f co n tra ctile p ro te in s a n d th e A
B A ba nd
a n d I b a n d s , th e H zo n e , a n d th e Z a n d M
Re la xa tion lin e s . (C) Th e re la xe d a n d co n tra cte d s ta te s
Actin o f th e m yo b ril s h o w in g th e p o s itio n o f
a ctin la m e n ts (b lu e ) b e tw e e n th e m yo s in
Myos in la m e n ts (p in k) in th e re la xe d m u s cle (to p )
a n d p u llin g o f th e Z m e m b ra n e s to wa rd e a ch
o th e r (b o tto m ) a s th e m u s cle co n tra cts .
C Contra ction D S a rcopla s mic re ticulum (D) Th e s arco p la sm ic re ticu lu m with T tu b u le s.

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C H A P T E R 1 Cell Structure and Function 25

represents the cell membrane. Embedded throughout or T tubules, which are extensions of the cell membrane
the sarcoplasm are the contractile elements actin and and run perpendicular to the muscle ber. The hollow por-
myosin, which are arranged in parallel bundles (i.e., tion or lumen of the T tubule is continuous with the extra-
m yo brils). Each myo bril consists of regularly repeat- cellular uid compartment. Action potentials, which are
ing units called sarcom eres along its length. rapidly conducted over the surface of the muscle ber, are
Sarcomeres, which are the structural and functional in turn propagated by the T tubules into the sarcoplasmic
units of striated muscle, extend from one Z line to reticulum. As the action potential moves through the lat-
another Z line (Fig. 1-17B). The central portion of the eral sacs, the sacs release calcium, initiating muscle con-
sarcomere contains the dark band (A band) consisting traction. The membrane of the sarcoplasmic reticulum also
mainly of myosin laments, with some overlap with has an active transport mechanism for pumping calcium
actin laments. Straddling the Z line, the lighter I band ions back into the reticulum. This prevents interactions
contains only actin laments; therefore, it takes two sar- between calcium ions and the actin and myosin myo la-
comeres to complete an I band. An H zone is found in ments after cessation of a muscle contraction.
the middle of the A band and represents the region where
only myosin laments are found. In the center of the H S ke le tal Mus cle Co ntractio n. M uscle contraction
zone is a thin, dark band, the M band or M line, pro- involves the sliding of the thick myosin and thin actin
duced by linkages between the myosin laments. Z lines laments over each other to produce shortening of the
consist of short elements that interconnect and provide muscle ber, while the actual length of the individual
the thin actin laments from two adjoining sarcomeres thick and thin laments remains unchanged. The thick
with an anchoring point. M uscle contraction involves myosin laments consist of a thin tail, which provides
the actin laments sliding inward among the myosin the structural backbone for the lament, and a globu-
laments (Fig. 1-17C). In the relaxed state, the ends of lar head that forms cross-bridges with the thin actin
the actin laments extend from two successive Z lines, laments (Fig. 1-18A). M yosin molecules are bundled
barely overlapping one another. In the contracted state, together side by side in the thick laments such that one
these actin laments have been pulled inward among the half have their heads toward one end of the lament and
myosin laments so their ends overlap one another. their tails toward the other end, and the other half are
The sarcoplasmic reticulum, which is comparable to arranged in the opposite manner. Each globular myosin
the smooth ER, is composed of longitudinal tubules that head contains a site able to bind to a complementary
run parallel to the muscle ber and surround each myo- site on the actin molecule. Besides the binding site for
bril (Fig. 1-17D). This network ends in enlarged, saclike actin, each myosin head has a separate active site that
regions called the lateral sacs or terminal cisternae. These catalyzes the breakdown of ATP to provide the energy
sacs store calcium that is released during muscle contrac- needed to activate the myosin head so it can form a
tion. A second system of tubules consists of the transverse cross-bridge with actin. After contraction, myosin also

ATP binding s ite

Cros s - 2
Myo s in bridge Actin binding s ite

Ta il He a d

Cros s -bridge a tta chme nt

A 1 3


Ac tin Tro p o n in c o m p le x
Cocking of myos in he a d P owe r s troke
Tropomyos in Actin TnI TnT

B C Cros s -bridge de ta chme nt
FIG U RE 1-1 8 . Mo le cu la r s tru ctu re o f th e th icke r m yo s in la m e n t (A) a n d th e th in n e r a ctin
la m e n t (B) o f s tria te d m u s cle . Th e th in la m e n t is a d o u b le -s tra n d e d h e lix o f a ctin m o le cu le s w ith
tro p o m yo s in a n d tro p o n in m o le cu le s lyin g a lo n g th e g ro ove s o f th e a ctin s tra n d s . (C) Se q u e n ce o f
e ve n ts invo lve d in s lid in g o f a d ja ce n t a ctin a n d m yo s in la m e n ts : (1) co ckin g o f th e m yo s in h e a d ,
w h ich o ccu rs a s a d e n o s in e trip h o s p h a te (ATP) is s p lit to a d e n o s in e d ip h o s p h a te (ADP); (2) cro s s -
b rid g e a tta ch m e n t; (3) p o w e r s tro ke d u rin g w h ich th e m yo s in h e a d b e n d s a s it m ove s th e a ctin
fo rwa rd ; a n d (4) cro s s -b rid g e d e ta ch m e n t, w h ich o ccu rs a s a n e w ATP a tta ch e s to th e m yo s in h e a d .

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26 U N I T 1 Cell and Tissue Function

binds ATP, thus breaking the linkage between actin and Inte rme dia te liga me nt bundle s
myosin. a tta che d to de ns e bodie s
The thin laments are composed mainly of actin, a
globular protein lined up in two rows that coil around
each other to form a long helical strand (Fig. 1-18B).
Associated with each actin lament are two regulatory De ns e bodie s
proteins, tropomyosin and troponin. Tropom yosin,
which lies in grooves of the actin strand, provides the
site for attachment of the globular heads of the myo-
sin lament. In the noncontracted state, troponin covers
the tropomyosin-binding sites and prevents formation
of cross-bridges between the actin and myosin. During
an action potential, calcium ions released from the sar-
coplasmic reticulum diffuse to the adjacent myo brils,
where they bind to troponin. The binding of calcium to
troponin uncovers the tropomyosin-binding sites such
that the myosin heads can attach and form cross-bridges.
M uscle contraction begins with activation of the
cross-bridges from the myosin laments and uncovering
of the tropomyosin-binding sites on the actin lament
(Fig. 1-18C). When activated by ATP, the heads of the
myosin laments swivel in a xed arc, much like the
oars of a boat, as they become attached to the actin la-
ment. During contraction, each myosin head undergoes
Contra cte d
its own cycle of movement, forming a bridge attachment
and releasing it, then moving to another site where the
same sequence of movement occurs. This pulls the thin
and thick laments past each other. Energy from ATP is Re la xe d
used to break the actin and myosin cross-bridges, stop-
FIG U RE 1-1 9 . S tru ctu re o f s m o o th m u scle s h o w in g th e d e n s e
ping the muscle contraction. After the linkage between
b o d ie s . In s m o o th m u s cle , th e fo rce o f co n tractio n is tra n sm itte d
actin and myosin, the concentration of calcium around to th e ce ll m e m b ra n e b y b u n d le s o f in te rm e d ia te b e rs .
the myo brils decreases as calcium is actively trans-
ported into the sarcoplasmic reticulum by a membrane
pump that uses energy derived from ATP. As with cardiac and skeletal muscle, smooth muscle
contraction is initiated by an increase in intracellular
S m o o th Mus cle calcium. H owever, smooth muscle differs from skeletal
muscle in the way its cross-bridges are formed. The sar-
Smooth muscle is often called involuntary m uscle coplasmic reticulum of smooth muscle is less developed
because its activity arises spontaneously or through the than in skeletal muscle, and no transverse tubules are
activity of the autonomic nervous system. Smooth mus- present. Smooth muscle relies on the entrance of extra-
cle is usually arranged in sheets or bundles and its con- cellular calcium for muscle contraction. This depen-
tractions are slower and more sustained than skeletal or dence on movement of extracellular calcium across the
cardiac muscle contractions. cell membrane during muscle contraction is the basis for
Smooth muscle cells are spindle shaped and smaller the action of calcium-blocking drugs used in the treat-
than skeletal muscle bers. Each smooth muscle cell has ment of cardiovascular disease.
one centrally positioned nucleus. Z bands and M lines Smooth muscle also lacks the calcium-binding regula-
are not present in smooth muscle bers, and the cross- tory protein troponin, which is found in skeletal and car-
striations are absent because the bundles of laments are diac muscle. Instead, it relies on another calcium-regulated
not parallel but criss-cross obliquely through the cell. mechanism involving the cytoplasmic protein calmodulin
Instead, the actin laments are attached to structures and an enzyme called myosin light chain kinase. Increased
called dense bodies. Some dense bodies are attached to calcium ions form a calciumcalmodulin complex that
the cell membrane, and others are dispersed in the cell binds to and activates myosin light chain kinase, which in
and linked together by structural proteins (Fig. 1-19). turn phosphorylates myosin to initiate contraction.
The lack of Z lines and regular overlapping of con-
tractile elements provide a greater range of tension N e r vo u s Tis s u e
development. This is important in hollow organs that
undergo changes in volume, with consequent changes in Nervous tissue is distributed throughout the body as an
the length of the smooth muscle bers in their walls. Even integrated communication system. Nerve cells, which
with the distention of a hollow organ, the smooth mus- develop from the embryonic ectoderm, are highly dif-
cle ber retains some ability to develop tension, whereas ferentiated and have long been considered incapable of
such distention would stretch skeletal muscle beyond the regeneration in postnatal life. However, it is now known
area where the thick and thin laments overlap. that parts of the brain, such as the hippocampus, contain

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C H A P T E R 1 Cell Structure and Function 27

areas where neurogenesis occurs from neural stem cells/ Ce ll Junctio ns

progenitor cells throughout life. Embryonic development
of the nervous system and the structure and functions of The junctions between tissue cells are important in govern-
the nervous system are discussed more fully in Chapter 34. ing the shape of the body, transmitting mechanical stresses
Structurally, nervous tissue consists of two cell types: from one cell to another, and creating pathways for commu-
nerve cells or neurons and supporting cells or neuroglia. nication. Cell junctions occur at many points in cell-to-cell
Most nerve cells consist of three parts: the soma or cell contact, but they are particularly plentiful and important
body, dendrites, and the axon. The cytoplasm- lled den- in epithelial tissue. These specialized junctions enable cells
drites, which are multiple elongated processes, receive to form barriers to the movement of water, solutes, and
and carry stimuli from the environment, sensory epithe- cells from one body compartment to the next. Three basic
lial cells, and other neurons to the cell. The axon, which types of intercellular junctions are observed: tight junctions,
is a single cytoplasm- lled process, is specialized for gen- adhering junctions, and gap junctions (Fig. 1-20).
erating and conducting nerve impulses away from the cell Tight or occluding junctions (i.e., zonula occludens),
body to other nerve cells, muscle cells, and glandular cells. which are found in epithelial tissue, seal the surface
N eurons can be classi ed as afferent and efferent membranes of adjacent cells together. This type of inter-
neurons according to their function. Afferent or sensory cellular junction prevents uids and materials such as
neurons carry information toward the central nervous macromolecules present in the intestinal contents from
system; they are involved in the reception of sensory entering the intercellular space.
information from the external environment and from Adhering junctions represent sites of strong adhesion
within the body. Efferent or motor neurons carry infor- between cells. The primary role of adhering junctions
mation away from the central nervous system (CN S); may be that of preventing cell separation. Adhering junc-
they are needed for control of muscle bers and endo- tions are not restricted to epithelial tissue; they provide
crine and exocrine glands. adherence between adjacent cardiac muscle cells as well.
Communication between neurons and effector organs, Adhering junctions are found as continuous, beltlike
such as muscle cells, occurs at specialized structures called adhesive junctions (i.e., zonula adherens) or scattered,
synapses. At the synapse, chemical messengers (i.e., neu- spotlike adhesive junctions, called desm osom es (i.e.,
rotransmitters) alter the membrane potential to conduct macula adherens). A special feature of the adhesion belt
impulses from one nerve to another or from a neuron to junction is that it provides an anchoring site to the cell
an effector cell. In addition, electrical synapses exist in membrane for actin laments. In epithelial desmosomes,
which nerve cells are linked through gap junctions that bundles of keratin intermediate laments (i.e., tono la-
permit the passage of ions from one cell to another. ments) are anchored to the junction on the cytoplasmic
N euroglia (glia means glue ) are the cells that sup- area of the cell membrane. A primary disease of desmo-
port neurons, form myelin, and have trophic and phago- somes is pemphigus, which is caused by antibody binding
cytic functions. Four types of neuroglia are found in the to the desmosome proteins and the resulting separation of
CN S: astrocytes, oligodendrocytes, microglia, and epen- neighboring cells. Affected persons have skin and mucous
dymal cells. Astrocytes are the most abundant of the membrane blistering. H em idesm osom es, which resemble
neuroglia. They have many long processes that surround a half desmosome, are another type of junction. They are
blood vessels in the CN S. They provide structural sup- found at the base of epithelial cells and help attach the
port for the neurons, and their extensions form a sealed epithelial cell to the underlying connective tissue.
barrier that protects the CN S. In last decade, investiga- G ap or nex us junctions involve the close adherence of
tions have established important roles for astrocytes in adjoining cell membranes with the formation of channels
the response of the brain to injury, calcium ion-based that connect the cytoplasm of the two cells. Because they
excitation, CN S metabolism, neural stem cell source, are low-resistance channels, gap junctions are impor-
bloodbrain barrier maintenance, and numerous dis- tant in cell-to-cell conduction of electrical signals (e.g.,
eases and pathological conditions. The oligodendrocytes between cells in sheets of smooth muscle or between
provide myelination of neuronal processes in the CN S. adjacent cardiac muscle cells, where they function as
The microglia are phagocytic cells that represent the electrical synapses). Gap junctions also enable ions and
mononuclear phagocytic system in the nervous system. small molecules to pass directly from one cell to another.
Ependymal cells line the cavities of the brain and spinal Extrace llular Matrix
cord and are in contact with the cerebrospinal uid. In
the peripheral nervous system, supporting cells consist Tissues are not made up solely of cells. A large part of
of the Schwann and satellite cells. The Schwann cells their volume is made up of an extracellular matrix. This
provide myelination of the axons and dendrites, and the matrix is composed of a variety of proteins and polysac-
satellite cells enclose and protect the dorsal root ganglia charides (i.e., polymers made up of many sugar mono-
and autonomic ganglion cells. mers). These proteins and polysaccharides are secreted
locally and are organized into a supporting meshwork
Ex t r a c e llu la r Tis s u e C o m p o n e n t s in close association with the cells that produced them.
The amount and composition of the matrix vary with
The discussion thus far has focused on the cellular com- the different tissues and their function. In bone, for
ponents of the different tissue types. Within tissues, cells example, the matrix is more plentiful than the cells that
are held together by cell junctions, and adhesion mol- surround it; in the brain, the cells are much more abun-
ecules form intercellular contacts. dant and the matrix is only a minor constituent.

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28 U N I T 1 Cell and Tissue Function

tight junction
(zonula occlude ns )

Microfila me nt bundle
(ma rgina l ba nd)

Tonofila me nt
Adhe s ion be lt De s mos ome
(zonula a dhe re ns ) (ma cula a dhe re ns )

Ba s e me nt Cha nne l
me mbra ne
He mide s mos ome

Ga p junction

FIG U RE 1-2 0 . Th re e typ e s o f in te rce llu la r ju n ctio n s fo u n d in e p ith e lia l tis s u e : th e co n tin u o u s
tig h t ju n ctio n (zo n u la o cclu d e n s ); th e a d h e rin g ju n ctio n , w h ich in clu d e s th e a d h e s io n b e lt (zo n u la
a d h e re n s ), d e s m o s o m e s (m a cu la a d h e re n s ), a n d h e m id e s m o s o m e s ; a n d th e ga p ju n ctio n .

Two main classes of extracellular macromolecules the cartilage matrix that lines the knee joint can support
make up the extracellular matrix. The rst is an amor- pressures of hundreds of atmospheres by this mechanism.
phous gel-like material called ground substance. Ground
substance is composed of polysaccharide chains of pro- Fibro us Prote ins. Three types of bers are found in the
teins called glycosam inoglycans (GAGs), which are usu- extracellular space: collagen, elastin, and reticular bers.
ally found linked to protein as proteoglycans. The second Collagen is the most common protein in the body. It is
type consists of the brous proteins (i.e., collagen and a tough, nonliving, white ber that serves as the struc-
elastin) and the brous adhesive proteins (i.e., bronectin tural framework for skin, ligaments, tendons, and many
and laminin) that are found in the basement membrane. other structures. Elastin acts like a rubber band; it can
M embers of each of these two classes of extracellular be stretched and then returns to its original form. Elastin
macromolecules come in a variety of shapes and sizes. bers are abundant in structures subjected to frequent
stretching, such as the aorta and some ligaments. Reticular
Ground Subs tance . The proteoglycan and GAG mol- bers are extremely thin bers that create a exible net-
ecules form a highly hydrated, gel-like substance, or tis- work in organs subjected to changes in form or volume,
sue gel, in which the brous proteins are embedded. The such as the spleen, liver, uterus, or intestinal muscle layer.
polysaccharide gel resists compressive forces; the collagen
bers strengthen and help organize the matrix; the rub- Ce ll Adhe s io n Mo le cule s
berlike elastin adds resilience; and the adhesive proteins
help cells attach to the appropriate part of the matrix. Important classes of extracellular macromolecules are the
Polysaccharides in the tissue gel are highly hydrophilic, cell adhesion molecules (CAMs). Cell adhesion molecules
and they form gels even at low concentrations. They can be cell-to-cell or cell-to-matrix adhesion molecules.
also produce a negative charge that attracts cations such There are four major classes of CAMs: cadherins, selec-
as sodium, which are osmotically active, causing large tins, integrins, and the immunoglobulin (Ig) superfamily
amounts of water to be sucked into the matrix. This cre- of proteins. These proteins are located on the cell surface
ates a swelling pressure, or turgor, that enables the matrix where they function as receptors, or they can be stored in
to withstand extensive compressive forces. For example, the cytoplasm. As receptors, CAMs can bind to similar or

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C H A P T E R 1 Cell Structure and Function 29

different molecules in other cells, providing for interaction superfamily proteins are the neural cell adhesion mol-
between the same cell types or different cell types. ecules (N -CAM s), which are expressed in a variety of
cells, including most nerve cells. During early develop-
Cadhe rins . Cadherins are the major CAM s responsible ment, N -CAM s play an important role in connecting the
for calcium-dependent cell-to-cell adhesion junctions. neurons of the developing nervous system.
The word cadherin is derived from the term calcium-
dependent adhesion protein. There are over 90
members of the cadherin superfamily. The rst three cad- S UM M A R Y C O N C EP TS
herins that were discovered were named according to the
main tissues in which they were found: the E-cadherins,
which are present in many types of epithelial cells; the Bo d y ce lls a re o rga n ize d in to fo u r b a s ic tis s u e
N -cadherins, which are present in nerve and muscle typ e s : e p ith e lia l, co n n e ctive , m u s cle , a n d
cells; and the P-cadherins, which are found on cells in the n e rvo u s . Th e e p ith e liu m cove rs a n d lin e s th e b o d y
placenta and epidermis. All are found in various other s u rfa ce s a n d fo rm s th e fu n ctio n a l co m p o n e n ts o f
tissues; N -cadherin, for example, is expressed in bro- g la n d u la r s tru ctu re s . Ep ith e lia l tis s u e is cla s s i e d
blasts, and E-cadherin is expressed in parts of the brain. in to th re e typ e s a cco rd in g to th e s h a p e o f th e
M ost cadherins function as transmembrane adhesive ce lls a n d th e n u m b e r o f la ye rs th a t a re p re s e n t:
proteins that indirectly link the actin cytoskeletons of s im p le , s tra ti e d , a n d p s e u d o s tra ti e d .
cells they join together, an arrangement that occurs in
adhering junctions. Cadherins also form desmosomes Co n n e ctive tis s u e s u p p o rts a n d co n n e cts b o d y
that interact with intermediate laments of the cyto- s tru ctu re s ; it fo rm s th e b o n e s a n d ca rtila g e ,
skeleton, rather than the actin laments. Cell-to-cell th e jo in t s tru ctu re s , th e d e rm is o f th e s kin , th e
interactions mediated by cadherins play a major role in s h e a th s o f b lo o d ve s s e ls a n d n e rve s , a d ip o s e
regulating cell motility, proliferation, and differentiation. tis s u e , lym p h a tic tis s u e s , a n d b lo o d . Fib ro b la s ts
a re th e m o s t a b u n d a n t co n n e ctive tis s u e ce lls .
S e le ctins . Selectins are cell surface carbohydrate- Th e y a re re s p o n s ib le fo r th e s yn th e s is o f co lla g e n ,
binding proteins (lectins) that mediate a variety of e la s tic, a n d re ticu la r b e rs a n d th e g e l-like g ro u n d
transient, cell-to-cell adhesion interactions in the blood- s u b s ta n ce th a t lls th e in te rce llu la r s p a ce s .
stream. They are found on activated endothelial cells of
blood vessels, on leukocytes, and on platelets. Selectins, Mu s cle tis s u e is a s p e cia lize d tis s u e d e s ig n e d
together with integrins and immunoglobulins, partici- fo r co n tra ctility. Th re e typ e s o f m u s cle tis s u e
pate in leukocyte movement through the endothelial lin- e xis t: s ke le ta l, ca rd ia c, a n d s m o o th . Actin a n d
ing of blood vessels during in ammation. m yo s in la m e n ts in te ra ct to p ro d u ce m u s cle
s h o rte n in g , a p ro ce s s a ctiva te d b y th e p re s e n ce
Inte g rins . Integrins usually assist in attaching epi- o f ca lciu m . In s ke le ta l m u s cle , ca lciu m is re le a s e d
thelial cells to the underlying basement membrane. fro m th e s a rco p la s m ic re ticu lu m in re s p o n s e
Extracellularly, they are attached to bronectin and lam- to a n a ctio n p o te n tia l. S m o o th m u s cle is o fte n
inin, the two major components of the basement mem- ca lle d invo lu n ta ry m u s cle b e ca u s e it co n tra cts
brane. Like the cadherins, their intracellular portion is
s p o n ta n e o u s ly o r th ro u g h th e a ctivity o f th e
linked to actin. O ne group of integrins is associated with
hemidesmosomes, whereas others are associated with the a u to n o m ic n e rvo u s s ys te m . It d iffe rs fro m
surface of white blood cells, macrophages, and platelets. s ke le ta l m u s cle in th a t its s a rco p la s m ic re ticu lu m
Integrins usually have a weak af nity for their ligands is le s s d e n e d a n d it d e p e n d s o n th e e n try o f
unless they are associated with cellular focal contacts and e xtra ce llu la r ca lciu m io n s fo r m u s cle co n tra ctio n .
hemidesmosomes. This allows some movement between Ne rvo us tiss ue is d e s ign e d fo r co m m un ica tion
cells except where a rm attachment is required to attach pu rp os e s a nd in clu de s th e n e u ron s , th e s u p p ortin g
epithelial cells to the underlying connective tissue.
ne ura l s tru cture s , a n d th e e pe nd ym a l ce lls tha t
Certain integrins play an important role in allowing
white blood cells to pass through the vessel wall, a process line th e ve n tricle s o f th e b ra in a n d th e s pina l ca na l.
called transm igration. Persons affected with leukocyte With in tis s u e s , ce lls a re h e ld to g e th e r b y ce ll
adhesion de ciency are unable to synthesize appropriate ju n ctio n s , w h ich a re e s p e cia lly p le n tifu l in
integrin molecules. As a result, they experience repeated e p ith e lia l tis s u e s . Th e re a re th re e b a s ic typ e s
bacterial infections because their white blood cells are o f ce ll ju n ctio n s : tig h t ju n ctio n s , a d h e rin g o r
not able to transmigrate through vessel walls. a d h e s ive -typ e ju n ctio n s , a n d ga p ju n ctio n s . Th e
a b ility o f ce lls to a d h e re to g e th e r (ce ll to ce ll)
Im m uno g lo bulin S upe rfam ily. The Ig superfamily
consists of a group of one or more immunoglobulin- o r to co m p o n e n ts o f th e e xtra ce llu la r m a trix
like adhesion proteins that are similar structurally to (ce ll to m a trix) is m e d ia te d b y ce ll a d h e s io n
those of antibody molecules. They have many func- m o le cu le s (ca d h e rin s , s e le ctin s , in te g rin s , a n d th e
tions outside the immune system that are unrelated im m u n o g lo b u lin s u p e rfa m ily o f p ro te in s ).
to immune defenses. The best-studied example of Ig

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Doherty GJ, M cM ahon H T. M echanisms and endocytosis. A nnu R ev

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Po rth Es s en tia ls Re s ources
A. H ypothesize how this information might be
used to design an oral rehydration solution for Explore the se additional re source s to e nhance le arning
someone who is suffering from diarrhea. for this chapte r:
NCLEX-Style Que stions and Othe r Re source s
on , http://the Point.lw w.com/PorthEsse ntials4e
Study Guide for Esse ntials of Pathophysiology
Conce pts in Action Animations
Adaptive Le arning | Powe re d by Pre pU, http://the point.lw w.com/
Alberts B, Johnson A, Lewis J, et al. M olecular Biology of the Cell.
5th ed. N ew York and London: Garland Publishing; 2008. pre pu
Alexeyev M , Shokolenko I, Wilson G, et al. The maintenance of
mitochondrial DN A integrity-critical analysis and update. Cold
Spring H arb Perspect Biol. 2013;5:a012641.

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Cellula r Responses to Persistent Stress
Ada pta tions of Growth a nd Differentia tion
Hyperpla sia
Meta pla sia
C h a p t e r
Dyspla sia
Intra cellula r Accumula tions
Pa thologic Ca lci ca tions
Ce llu la r
Dystrophic Ca lci ca tion
Meta sta tic Ca lci ca tion
Re s p o n s e s t o
Cell Injury, Dea th, a nd Senescence
Ca uses of Cell Injury
S t re s s , In ju r y,
Injury from Physica l Agents
Ra dia tion Injury a n d Ag in g
Chemica l Injury
Injury from Biologic Agents
Injury from N utritiona l Imba la nces
Mecha nisms of Cell Injury
Free Ra dica l Injury
Hypoxic Cell Injury
I n their simplest form, all diseases exert their effects on
the smallest living unit of the bodythe cell. When
confronted with stresses that endanger its normal struc-
Impa ired Ca lcium Homeosta sis ture and function, the cell undergoes adaptive changes
Reversible Cell Injury a nd Cell Dea th that permit survival and maintenance of function. It is
Reversible Cell Injury only when the stress is overwhelming or adaptation is
Progra mmed Cell Dea th ineffective that injury, maladaptive changes, and cell
N ecrosis death occur. Biologic aging produces its own changes in
cell structure and function.
Cellula r Aging
Replica tive Senescence
G enetic In uences C e llu la r Re s p o n s e s t o
Accumula tion of Environmenta l a nd Genetic
Da ma ge
P e r s is t e n t S t r e s s
Syndromes of Prema ture Aging
Cells adapt to changes in the internal environment just
as the total organism adapts to changes in the external
environment. Cells may adapt by undergoing changes
in size, number, and type. These changes, occurring sin-
gly or in combination, may lead to atrophy, hypertro-
phy, hyperplasia, metaplasia, and dysplasia (Fig. 2-1).
Cellular stresses also include intracellular accumula-
tions and storage of products in abnormal amounts.1,2

Ad a p t a t io n s o f G ro w t h a n d
D iff e r e n t ia t io n
N umerous molecular mechanisms mediate cellular
adaptation, including factors in the cellular microen-
vironment and the cells themselves. These mechanisms
largely depend on extracellular signals and cues, which
in turn activate intracellular signaling mechanisms
transmitted by chemical messengers that alter gene
expression. O nce the primary stimulus for adaptation is
removed, the cause of changing gene expression patterns
is removed and the cell may revert back to its previous
state. Whether adaptive cellular changes are normal or
abnormal depends in part on whether the response was
mediated by an appropriate stimulus. N ormal adaptive
responses occur in response to need and an appropriate

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32 U N I T 1 Cell and Tissue Function

level of functioning that is compatible with survival.1,2

This decrease in cell size is called atrophy. Cells that
Nucle us are atrophied reduce oxygen consumption and other
cellular functions by decreasing the number and size of
Ba s e me nt their organelles and other structures. There are fewer
Norma l ce lls me mbra ne mitochondria, myo laments, and endoplasmic reticu-
lum structures. When a suf cient number of cells are
involved, the entire tissue atrophies.
Cell size, particularly in muscle tissue, is related to
workload. As the workload of a cell declines, oxygen con-
Atrophy sumption and protein synthesis decrease. Furthermore,
proper muscle mass is maintained by suf cient levels
of insulin/insulin-like growth factor-1 (IGF-1). When
insulin/IGF-1 levels are low or catabolic signals are
present, muscle atrophy occurs by a variety of mecha-
nisms. O ne such mechanism is increased proteolysis by
the ubiquitin-proteasome system, in which intracellular
Hype rtrophy proteins destined for destruction are covalently bonded
to a small protein called ubiquitin and then degraded
by small cytoplasmic organelles called proteasom es (see
Chapter 1). O ther mechanisms, such as reduced syn-
thetic (anabolic) processes and apoptosis (programmed
cell death), are also involved (to be discussed).3
The general causes of atrophy can be grouped into
Hype rpla s ia
ve categories: (1) disuse, (2) denervation, (3) loss of
endocrine stimulation, (4) inadequate nutrition, and
(5) ischemia or decreased blood ow. Disuse atrophy
occurs when there is a reduction in skeletal muscle use.
An extreme example of disuse atrophy is seen in the
muscles of extremities that have been encased in casts.
Because atrophy is adaptive and reversible, muscle size
is restored after the cast is removed and muscle use is
Me ta pla s ia resumed. Denervation atrophy is a form of disuse atro-
phy that occurs in the muscles of paralyzed limbs. Lack
of endocrine stimulation produces a form of disuse atro-
phy. In women, the loss of estrogen stimulation during
menopause results in atrophic changes in the reproduc-
tive organs. With malnutrition and decreased blood
ow, cells decrease their size and energy requirements as
a means of survival.

Hype rtro phy

H ypertrophy represents an increase in cell size, and with
Dys pla s ia it an increase in the amount of functioning tissue mass.
FIG U RE 2 -1. Ad a p tive ce ll a n d tis s u e re s p o n s e s invo lvin g It results from an increased workload imposed on an
a ch a n g e in ce ll s ize (hyp e rtro p hy a n d a tro p hy), n u m b e r organ or body part and is commonly seen in cardiac
(hyp e rp la s ia ), ce ll typ e (m e ta p la s ia ), o r s ize , s h a p e , a n d and skeletal muscle tissue, which cannot adapt to an
o rga n iza tio n (d ys p la s ia ). (Fro m An a to m ica l Ch a rt Co m p a ny. increase in workload through mitotic division and for-
Atla s o f Pa th o p hys io lo g y. S p rin g h o u s e , PA: S p rin g h o u s e ; mation of more cells. H ypertrophy involves an increase
20 02:4.) in the functional components of the cell that allows it
to achieve equilibrium between demand and functional
capacity. For example, as muscle cells hypertrophy,
stimulus. After the need has been removed, the adaptive additional actin and myosin laments, cell enzymes, and
response ceases. adenosine triphosphate (ATP) are synthesized.
H ypertrophy may occur as the result of normal phys-
iologic or abnormal pathologic conditions. The increase
Atro phy
in muscle mass associated with exercise is an example of
When confronted with a decrease in work demands or physiologic hypertrophy. Pathologic hypertrophy occurs
adverse environmental conditions, most cells are able to as the result of disease conditions and may be adaptive
revert to a smaller size and a lower and more ef cient or compensatory. Examples of adaptive hypertrophy are

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C H A P T E R 2 Cellular Responses to Stress, Injury, and Aging 33

the thickening of the urinary bladder from long-con- signal molecules can alter gene expression controlling the
tinued obstruction of urinary out ow and myocardial size and assembly of the contractile proteins in hypertro-
hypertrophy from valvular heart disease or hyperten- phied myocardial cells. For example, the hypertrophied
sion. Compensatory hypertrophy is the enlargement myocardial cells of well-trained athletes have propor-
of a remaining organ or tissue after a portion has been tional increases in width and length. This is in contrast to
surgically removed or rendered inactive. For instance, if the hypertrophy that develops in dilated cardiomyopathy,
one kidney is removed, the remaining kidney enlarges to in which the hypertrophied cells have a relatively greater
compensate for the loss. increase in length than width. In pressure overload, as
The initiating signals for hypertrophy appear to occurs with hypertension, the hypertrophied cells have
be complex and related to ATP depletion, mechanical greater width than length.5 It is anticipated that further
forces such as stretching of the muscle bers, activa- elucidation of the signal pathways that determine the
tion of cell degradation products, and hormonal fac- adaptive and nonadaptive features of cardiac hypertro-
tors. In the case of the heart, initiating signals can be phy will lead to new targets for treatment.
divided into two broad categories: (1) biomechanical
and stretch-sensitive mechanisms and (2) neurohumoral Hype rplas ia
mechanisms associated with the release of hormones,
growth factors, cytokines, and chemokines. 4 Internal H yperplasia refers to an increase in the number of cells in
stretch-sensitive receptors for the biochemical signals an organ or tissue. It occurs in tissues with cells that are
and an array of membrane-bound receptors for the spe- capable of mitotic division, such as the epidermis, intes-
ci c neurohumoral ligands, such as IGF-1 and epidermal tinal epithelium, and glandular tissue. 1,2 Certain cells,
growth factor (EGF), activate speci c signal transduc- such as neurons, rarely divide and therefore have little (if
tion pathways. These pathways control myocardial any) capacity for hyperplastic growth. There is evidence
growth by altering gene expression to increase protein that hyperplasia involves activation of genes controlling
synthesis and reduce protein degradation, thereby caus- cell proliferation and the presence of intracellular mes-
ing hypertrophic enlargement of the heart. A limit is sengers that control cell replication and growth. As with
eventually reached beyond which further enlargement other normal adaptive cellular responses, hyperplasia is
of the tissue mass is no longer able to compensate for a controlled process that occurs in response to an appro-
the increased work demands. The limiting factors for priate stimulus and ceases after the stimulus has been
continued hypertrophy might be related to limitations in removed.
blood ow. In hypertension, for example, the increased The stimuli that induce hyperplasia may be physio-
workload required to pump blood against an elevated logic or nonphysiologic. There are two common types of
arterial pressure results in a progressive increase in left physiologic hyperplasia: hormonal and compensatory.
ventricular muscle mass and need for coronary blood Breast and uterine enlargement during pregnancy are
ow (Fig. 2-2). examples of a physiologic hyperplasia that results from
There continues to be interest in the signaling path- estrogen stimulation. The regeneration of the liver that
ways that control the arrangement of contractile elements occurs after partial hepatectomy (i.e., partial removal of
in myocardial hypertrophy. Research suggests that certain the liver) is an example of compensatory hyperplasia.
H yperplasia is also an important response of connec-
tive tissue in wound healing, during which proliferat-
ing broblasts and blood vessels contribute to wound
repair. Although hypertrophy and hyperplasia are two
distinct processes, they may occur together and are
often triggered by the same mechanism.1 For example,
the pregnant uterus undergoes both hypertrophy and
hyperplasia as a result of estrogen stimulation.
M ost forms of nonphysiologic hyperplasia are due to
excessive hormonal stimulation or the effects of growth
factors on target tissues.2 Excessive estrogen production
can cause endometrial hyperplasia and abnormal men-
strual bleeding (see Chapter 40). Benign prostatic hyper-
plasia, which is a common disorder of men older than
50 years of age, is thought to be related to the action of
androgens (see Chapter 39). Skin warts are an example
of hyperplasia caused by growth factors produced by
certain viruses, such as the papillomaviruses.
FIG U RE 2 -2 . Myo ca rd ia l hyp e rtro p hy. Cro s s -s e ctio n o f
th e h e a rt in a p a tie n t w ith lo n g -s ta n d in g hyp e rte n s io n .
(Fro m S tra ye r DS , Ru b in E. Ce ll a d a p ta tio n , ce ll in ju ry a n d Me taplas ia
ce ll d e a th . In : Ru b in R, S tra ye r DS , e d s . Ru b ins Pa th o lo g y:
Clin ico p a th o lo g ic Fo u n d a tio n s o f Me d icin e . 6th e d . M etaplasia represents a reversible change in which one
Ph ila d e lp h ia , PA: Wo lte rs Klu w e r He a lth | Lip p in co tt adult cell type (epithelial or mesenchymal) is replaced
Willia m s & Wilkin s ; 2012:4.) by another adult cell type. 1,2 These changes are thought

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34 U N I T 1 Cell and Tissue Function

to involve the reprogramming of undifferentiated stem products, such as those resulting from inborn errors of
cells that are present in the tissue undergoing the meta- metabolism; and (3) exogenous products, such as envi-
plastic changes. ronmental agents and pigments that cannot be broken
M etaplasia usually occurs in response to chronic down by the cell. 2 These substances may accumulate
irritation and in ammation and allows for substitu- transiently or permanently, and they may be harmless
tion of cells that are better able to survive under cir- or, in some cases, toxic.
cumstances in which a more fragile cell type might Under some conditions cells may accumulate abnor-
succumb. H owever, the conversion of cell type never mal amounts of various substances, some of which may
oversteps the boundaries of the primary tissue type be harmless while others may be associated with vary-
(e.g., one type of epithelial cell may be converted to ing degrees of injury. Frequently, normal substances
another type of epithelial cell, but not to a connective accumulate because they are synthesized at a rate that
tissue cell). An example of metaplasia is the adaptive exceeds their metabolism or removal. An example of
substitution of strati ed squamous epithelial cells for this type of process is a condition called fatty liver,
the ciliated columnar epithelial cells in the trachea and which is due to intracellular accumulation of triglyc-
large airways of a habitual cigarette smoker. Although erides. Liver cells normally contain some fat, which
the squamous epithelium is better able to survive in is either oxidized and used for energy or converted to
these situations, the protective function that the cili- triglycerides. This fat is derived from free fatty acids
ated epithelium provides for the respiratory tract is released from adipose tissue. Abnormal accumulation
lost. Also, continued exposure to the in uences that occurs when the delivery of free fatty acids to the liver
cause metaplasia may predispose to cancerous trans- is increased, as in starvation and diabetes mellitus,
formation of the metaplastic epithelium. or when the intrahepatic metabolism of lipids is dis-
turbed, as in alcoholism.
Dys plas ia Intracellular accumulation can result from genetic
disorders that disrupt the enzymatic degradation of
D ysplasia is characterized by deranged cell growth of
selected substances or their transport to other sites. A
a speci c tissue that results in cells that vary in size,
normal enzyme may be replaced with an abnormal one,
shape, and organization. M inor degrees of dyspla-
resulting in the formation of a substance that cannot
sia are associated with chronic irritation or in am-
be used or eliminated from the cell, or an enzyme may
mation. 1 The pattern is most frequently encountered
be missing, so that an intermediate product accumulates
in areas of metaplastic squamous epithelium of the
in the cell. For example, there are at least 10 genetic
respiratory tract and uterine cervix. Although dyspla-
disorders that affect glycogen metabolism, most of
sia is abnormal, it is adaptive in that it is potentially
which lead to the accumulation of intracellular glycogen
reversible after the irritating cause has been removed.
stores. In the most common form of this disorder, von
Dysplasia is strongly implicated as a precursor of can-
Gierke disease, large amounts of glycogen accumulate
cer. In cancers of the respiratory tract and the uterine
in the liver and kidneys because of a de ciency of the
cervix, dysplastic changes have been found adjacent to
enzyme glucose-6-phosphatase. Without this enzyme,
the foci of cancerous transformation. Through the use
glycogen cannot be broken down to form glucose. The
of the Papanicolaou (Pap) test, it has been documented
disorder leads not only to an accumulation of glycogen
that cancer of the uterine cervix develops in a series
but also to a reduction in blood glucose levels. In Tay-
of incremental epithelial changes ranging from severe
Sachs disease, another genetic disorder, abnormal lipids
dysplasia to invasive cancer (discussed in Chapter 40).
accumulate in the brain and other tissues, causing motor
H owever, dysplasia is an adaptive process and as such
and mental deterioration beginning at approximately 6
does not necessarily lead to cancer. In many cases, the
months of age, followed by death at 2 to 3 years of age
dysplastic cells revert to their former structure and
(see Chapter 6).
Pigments are colored substances that may accumu-
late in cells. They can be endogenous (i.e., arising from
within the body) or exogenous (i.e., arising from out-
In t r a c e llu la r Ac c u m u la t io n s side the body). Icterus, also called jaundice, is charac-
Intracellular accumulations represent the buildup of terized by a yellow discoloration of tissue due to the
substances that cells cannot immediately use or elimi- retention of bilirubin, an endogenous bile pigment. This
nate. The substances may accumulate in the cytoplasm condition may occur because of increased bilirubin pro-
(frequently in the lysosomes) or in the nucleus. In some duction from red blood cell destruction, obstruction of
cases the accumulation may be an abnormal substance bile passage into the intestine, or diseases that affect
that the cell has produced, and in other cases the cell the livers ability to remove bilirubin from the blood.
may be storing exogenous materials or products of Lipofuscin is a yellow-brown pigment that results from
pathologic processes occurring elsewhere in the body. the accumulation of the indigestible residues produced
These substances can be grouped into three categories: during normal turnover of cell structures (Fig. 2-3). The
(1) normal body substances, such as lipids, proteins, accumulation of lipofuscin increases with age and is
carbohydrates, melanin, and bilirubin, that are present sometimes referred to as the w ear-and-tear pigm ent. It is
in abnormally large amounts; (2) abnormal endogenous more common in heart, nerve, and liver cells than other

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C H A P T E R 2 Cellular Responses to Stress, Injury, and Aging 35

FIG U RE 2 -3 . Accu m u la tio n o f in tra ce llu la r lip o fu s cin .

A p h o to m icro g ra p h o f th e live r o f a n 80-ye a r-o ld m a n s h o w s
g o ld e n cyto p la s m ic g ra n u le s , w h ich re p re s e n t lys o s o m a l
s to ra g e o f lip o fu s cin . (Fro m S tra ye r DS , Ru b in E. Ce ll
a d a p ta tio n , ce ll in ju ry a n d ce ll d e a th . In : Ru b in R, S tra ye r
DS , e d s . Ru b ins Pa th o lo g y: Clin ico p a th o lo g ic Fo u n d a tio n s o f
FIG U RE 2 -4 . Ca lci c a o rtic s te n o s is . La rg e d e p o s its o f ca lciu m
Me d icin e . 6th e d . Ph ila d e lp h ia , PA: Wo lte rs Klu w e r He a lth |
s a lts a re e vid e n t in th e cu s p s a n d fre e m a rg in s o f th e th icke n e d
Lip p in co tt Willia m s & Wilkin s ; 2012:21.)
a o rtic va lve a s vie w e d fro m a b ove . (Fro m S tra ye r DS , Ru b in E.
Ce ll a d a p ta tio n , ce ll in ju ry a n d ce ll d e a th . In : Ru b in R, S tra ye r
DS , e d s . Ru b ins Pa th o lo g y: Clin ico p a th o lo g ic Fo u n d a tio n s o f
tissues and is seen more often in conditions associated Me d icin e . 6th e d . Ph ila d e lp h ia , PA: Wo lte rs Klu w e r He a lth |
Lip p in co tt Willia m s & Wilkin s ; 2012:13.)
with atrophy of an organ.
One of the most common exogenous pigments is
carbon in the form of coal dust. In coal miners or per-
sons exposed to heavily polluted environments, the gritty sand-like grains to rm, hard, rock-like mate-
accumulation of carbon dust blackens the lung tissue and rial. The pathogenesis of dystrophic calci cation
may cause serious lung disease. The formation of a blue involves the intracellular or extracellular formation of
lead line along the margins of the gum is one of the diag- crystalline calcium phosphate. The components of the
nostic features of lead poisoning. Tattoos are the result of calcium deposits are derived from the bodies of dead
insoluble pigments introduced into the skin, where they or dying cells as well as from the circulation and inter-
are engulfed by macrophages and persist for a lifetime. stitial uid.
The signi cance of intracellular accumulations Dystrophic calci cation is commonly seen in ath-
depends on the cause and severity of the condition. M any eromatous lesions of advanced atherosclerosis, areas of
accumulations, such as lipofuscin and mild fatty changes, injury in the aorta and large blood vessels, and damaged
have no effect on cell function. Some conditions, such as heart valves. While the presence of calci cation may
the hyperbilirubinemia that causes jaundice, are revers- only indicate the presence of previous cell injury, as in
ible. O ther disorders, such as glycogen storage diseases, healed tuberculosis lesions, it is also a frequent cause
produce accumulations that result in organ dysfunction of organ dysfunction. For example, calci cation of the
and other alterations in physiologic function. aortic valve is a frequent cause of aortic stenosis in the
elderly (Fig. 2-4).

P a t h o lo g ic C a lc i c a t io n s Me tas tatic Calci catio n

Pathologic calci cation involves the abnormal tis- In contrast to dystrophic calci cation, which occurs in
sue deposition of calcium salts, together with smaller injured tissues, metastatic calci cation occurs in normal
amounts of iron, magnesium, and other minerals. It tissues as the result of increased serum calcium levels
is known as dystrophic calci cation when it occurs in (hypercalcemia). Almost any condition that increases
dead or dying tissue and as m etastatic calci cation when the serum calcium level can lead to calci cation in
it occurs in normal tissue. 1,2 inappropriate sites such as the lung, renal tubules, and
blood vessels. The major causes of hypercalcemia are
hyperparathyroidism, either primary or secondary to
Dys tro phic Calci catio n
phosphate retention in renal failure; increased release of
Dystrophic calci cation represents the macroscopic calcium from bone as in immobilization, Paget disease,
deposition of calcium salts in injured tissue. It is often or cancer with metastatic bone lesions; and vitamin D
visible to the naked eye as deposits that range from intoxication.

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36 U N I T 1 Cell and Tissue Function

C a u s e s o f C e ll In ju ry
Cell damage can occur in many ways. For purposes of
discussion, the ways by which cells are injured have
Ce lls a d a p t to ch a n g e s in th e ir e nviro n m e n t a n d been grouped into ve categories: (1) injury from physi-
in th e ir w o rk d e m a n d s b y ch a n g in g th e ir s ize , cal agents, (2) radiation injury, (3) chemical injury, (4)
n u m b e r, a n d ch a ra cte ris tics . Th e s e a d a p tive injury from biologic agents, and (5) injury from nutri-
ch a n g e s a re co n s is te n t w ith th e n e e d s o f th e ce ll tional imbalances.
a n d o ccu r in re s p o n s e to a n a p p ro p ria te s tim u lu s .
Th e ch a n g e s a re u s u a lly re ve rs e d a fte r th e
Injury fro m Phys ical Age nts
s tim u lu s h a s b e e n w ith d ra w n . Physical agents responsible for cell and tissue injury
include mechanical forces, extremes of temperature,
Wh e n co n fro n te d w ith a d e cre a s e in w o rk
and electrical forces. They are common causes of inju-
d e m a n d s o r a d ve rs e e n viro n m e n ta l co n d itio n s ,
ries due to environmental exposure, occupational and
ce lls a tro p h y, o r re d u ce in s ize . Wh e n co n fro n te d transportation accidents, and physical violence and
w ith a n in cre a s e in w o rk d e m a n d s th e y u n d e rg o assault.
h yp e rtro p h y, a n in cre a s e in s ize . An in cre a s e
in th e n u m b e r o f ce lls in a n o rg a n o r tis s u e is Me chanical Fo rce s . Injury or trauma due to mechani-
ca lle d h yp e rp la s ia . cal forces occurs as the result of body impact with
another object. The body or the mass can be in motion
Me ta p la s ia o ccu rs in re s p o n s e to ch ro n ic
or, as sometimes happens, both can be in motion at the
irrita tio n a n d re p re s e n ts th e s u b s titu tio n o f ce lls time of impact. These types of injuries split and tear
o f a typ e th a t a re b e tte r a b le to s u rvive u n d e r tissue, fracture bones, injure blood vessels, and disrupt
circu m s ta n ce s in w h ich a m o re fra g ile ce ll typ e blood ow.
m ig h t s u ccu m b . Dys p la s ia is ch a ra cte rize d b y
d e ra n g e d ce ll g ro w th o f a s p e ci c tis s u e th a t Extre m e s o f Te m pe rature . Extremes of heat and
re s u lts in ce lls th a t va ry in s ize , s h a p e , a n d cold cause damage to the cell, its organelles, and its
a p p e a ra n ce . It is o fte n a p re cu rs o r o f ca n ce r. enzyme systems. Exposure to low-intensity heat (43C
to 46C), such as occurs with partial-thickness burns
Un d e r s o m e circu m s ta n ce s , ce lls m a y and severe heat stroke, causes cell injury by inducing
a ccu m u la te a b n o rm a l a m o u n ts o f va rio u s vascular injury, accelerating cell metabolism, inacti-
s u b s ta n ce s . If th e a ccu m u la tio n re e cts a vating temperature-sensitive enzymes, and disrupting
co rre cta b le s ys te m ic d is o rd e r, s u ch a s th e the cell membrane. With more intense heat, coagula-
h yp e rb iliru b in e m ia th a t ca u s e s ja u n d ice , th e tion of blood and tissue proteins occurs. Exposure
a ccu m u la tio n is re ve rs ib le . If th e d is o rd e r to cold increases blood viscosity and induces vaso-
ca n n o t b e co rre cte d , a s o fte n o ccu rs in m a ny constriction by direct action on blood vessels and
in b o rn e rro rs o f m e ta b o lis m , th e ce lls b e co m e through re ex activity of the sympathetic nervous
o ve rlo a d e d , ca u s in g ce ll in ju ry a n d d e a th .
system. The resultant decrease in blood ow may lead
to hypoxic tissue injury, depending on the degree and
Pa th o lo g ic ca lci ca tio n in vo lve s th e a b n o rm a l duration of cold exposure. Injury from freezing prob-
tis s u e d e p o s itio n o f ca lciu m s a lts . Dys tro p h ic ably results from a combination of ice crystal forma-
ca lci ca tio n o ccu rs in d e a d o r d yin g tis s u e , tion and vasoconstriction. The decreased blood ow
w h e re a s m e ta s ta tic ca lci ca tio n o ccu rs in leads to capillary stasis and arteriolar and capillary
n o rm a l tis s u e s a s th e re s u lt o f e le va te d s e ru m thrombosis. Edema results from increased capillary
ca lciu m le ve ls . permeability.

Ele ctrical Fo rce s . Injuries due to electrical forces can

affect the body through extensive tissue injury and
disruption of neural and cardiac impulses. The effect
of electricity on the body is mainly determined by its
C e ll In ju ry, D e a t h , a n d voltage, the type of current (i.e., direct or alternat-
Senescence ing), its amperage, the resistance of the intervening
tissue, the pathway of the current, and the duration
Cells can be injured in many ways. The extent to which of exposure. 6
any injurious agent can cause reversible or irreversible Lightning and high-voltage wires that carry sev-
cell injury and death depends in large measure on the eral thousand volts produce the most severe damage. 2
intensity and duration of the injury and the type of cell Alternating current (AC) is usually more dangerous
that is involved, as well as variables such as blood sup- than direct current (DC) because it causes violent muscle
ply, nutritional status, and regenerative capacity. Cell contractions, preventing the person from releasing the
injury and death are ongoing processes, and in the electrical source and sometimes resulting in fractures
healthy state, they are balanced by cell renewal. and dislocations. In electrical injuries, the body acts as

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C H A P T E R 2 Cellular Responses to Stress, Injury, and Aging 37

a conductor of the electrical current. The current enters of radiation energy. Radiation energy with frequen-
the body from an electrical source, such as an exposed cies above the ultraviolet (UV) range is called ionizing
wire, and passes through the body and exits to another radiation because the photons have enough energy to
conductor, such as the moisture on the ground or a piece knock electrons off atoms and molecules. N onionizing
of metal the person is holding. The pathway that a cur- radiation refers to radiation energy at frequencies below
rent takes is critical because the electrical energy disrupts those of visible light. Ultraviolet radiation represents
impulses in excitable tissues. Current ow through the the portion of the spectrum of electromagnetic radiation
brain may interrupt impulses from respiratory centers in just above the visible range.
the brain stem, and current ow through the chest may
cause fatal cardiac arrhythmias. Io nizing Radiatio n. Ionizing radiation affects cells by
The resistance to the ow of current in electrical cir- causing ionization of molecules and atoms in the cell,
cuits transforms electrical energy into heat. This is why by directly hitting the target molecules in the cell, or by
the elements in electrical heating devices are made of producing free radicals (highly reactive chemical species)
highly resistive metals. M uch of the tissue damage pro- that destabilize molecules in critical cell components. 2,7
duced by electrical injuries is caused by heat production It can immediately kill cells, interrupt cell replication, or
in tissues that have the highest electrical resistance.2,7 cause a variety of genetic mutations, which may or may
Resistance to electrical current varies from the greatest not be lethal. M ost radiation injury is caused by local-
to the least in bone, fat, tendons, skin, muscles, blood, ized irradiation that is used in the treatment of cancer
and nerves. The most severe tissue injury usually occurs (see Chapter 7). Except for unusual circumstances such
at the skin sites where the current enters and leaves as the use of high-dose irradiation that precedes bone
the body (Fig. 2-5). After electricity has penetrated the marrow transplantation, exposure to whole-body irra-
skin, it rapidly passes through the body along the lines diation is rare.
of least resistancethrough body uids and nerves. The injurious effects of ionizing radiation vary with
Degeneration of vessel walls may occur, and thrombi the dose, dose rate (a single large dose can cause greater
may form as current ows along the blood vessels. This injury than divided or fractionated doses), and the dif-
can cause extensive muscle and deep tissue injury. Thick, ferential sensitivity of the exposed tissue to radiation
dry skin is more resistant to the ow of electricity than injury. Because of the effect on deoxyribonucleic acid
thin, wet skin. It is generally believed that the greater the (DN A) synthesis and interference with mitosis, rapidly
skin resistance, the greater is the amount of local skin dividing cells of the bone marrow and intestine are much
burn; and the less the resistance, the greater are the deep more vulnerable to radiation injury than tissues such as
and systemic effects. bone and skeletal muscle. O ver time, occupational and
accidental exposure to ionizing radiation can result in
Radiatio n Injury increased risk for the development of various types of
cancers, including skin cancers, leukemia, osteogenic
Electromagnetic radiation comprises a wide spectrum of sarcomas, and lung cancer.
wave-propagated energy, ranging from ionizing gamma M any of the clinical manifestations of radiation injury
rays to radiofrequency waves. A photon is a particle result from acute cell injury, dose-dependent changes in
the blood vessels that supply the irradiated tissues, and
brotic tissue replacement. The cells initial response
to radiation injury involves swelling, disruption of the
mitochondria and other organelles, alterations in the
cell membrane, and marked changes in the nucleus. The
endothelial cells in blood vessels are particularly sensitive
to irradiation. During the immediate post-irradiation
period, only vessel dilatation is apparent (e.g., the ini-
tial erythema of the skin after radiation therapy). Later
or with higher levels of radiation, destructive changes
occur in small blood vessels such as the capillaries and
venules. Acute reversible necrosis is represented by such
disorders as radiation cystitis, dermatitis, and diarrhea
from enteritis. M ore persistent damage can be attributed
to acute necrosis of tissue cells that are not capable of
regeneration, or because of chronic ischemia. Chronic
effects of radiation damage are characterized by bro-
sis and scarring of tissues and organs in the irradiated
FIG U RE 2 -5 . Ele ctrica l b u rn o f th e s kin . Th e victim wa s
e le ctro cu te d a fte r a tte m p tin g to s to p a fa ll fro m a la d d e r
area (e.g., interstitial brosis of the heart and lungs after
b y g ra s p in g a h ig h -vo lta g e lin e . (Fro m S tra ye r DS , Ru b in E. irradiation of the chest). Because the radiation delivered
Enviro n m e n ta l a n d n u tritio n a l p a th o lo g y. In : Ru b in R, S tra ye r in radiation therapy inevitably travels through the skin,
DS , e d s . Ru b ins Pa th o lo g y: Clin ico p a th o lo g ic Fo u n d a tio n s o f radiation dermatitis is common. There may be necrosis
Me d icin e . 6th e d . Ph ila d e lp h ia , PA: Wo lte rs Klu w e r He a lth | of the skin, impaired wound healing, and chronic radia-
Lip p in co tt Willia m s & Wilkin s ; 2012:313.) tion dermatitis.

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38 U N I T 1 Cell and Tissue Function

Ultravio le t Radiatio n. Ultraviolet radiation contains manufacturing, causes little damage until it is metabo-
increasingly energetic rays that are powerful enough to lized by liver enzymes to a highly reactive free radical
disrupt intracellular bonds, cause sunburn, and increase that is extremely toxic to liver cells.
the risk of skin cancers (see Chapter 46). The degree
of risk depends on the type of UV rays, the intensity Drug s . M any drugsalcohol, prescription drugs, over-
of exposure, and the amount of protective melanin pig- the-counter drugs, and street drugsare capable of
ment in the skin. Skin damage induced by UV radiation directly or indirectly damaging tissues. Ethyl alcohol can
is thought to be caused by reactive oxygen species and harm the gastric mucosa, liver (see Chapter 30), develop-
by damage to melanin-producing processes in the skin. ing fetus (see Chapter 6), and other organs. Antineoplastic
Ultraviolet radiation also damages DN A, resulting in (anticancer) and immunosuppressant drugs can directly
the formation of pyrimidine dimers (i.e., the insertion injure cells. O ther drugs produce metabolic end prod-
of two identical pyrimidine bases into replicating DN A ucts that are toxic to cells. Acetaminophen, a commonly
instead of one). O ther forms of DN A damage include used over-the-counter analgesic drug, is detoxi ed in the
the production of single-stranded breaks and forma- liver, where small amounts of the drug are converted
tion of DN Aprotein cross-links. N ormally, errors that to a highly toxic metabolite. This metabolite is detoxi-
occur during DN A replication are repaired by enzymes ed by a metabolic pathway that uses a substance (i.e.,
that remove the faulty section of DN A and repair the glutathione) normally present in the liver. When large
damage. The importance of DN A repair in protecting amounts of the drug are ingested, this pathway becomes
against UV radiation injury is evidenced by the vul- overwhelmed and toxic metabolites accumulate, causing
nerability of persons who lack the enzymes needed to massive liver necrosis.
repair UV-induced DN A damage. In a genetic disorder
called x eroderm a pigm entosum , an enzyme needed to Le ad Toxicity. Lead is a particularly toxic metal. Small
repair sunlight-induced DN A damage is lacking. This amounts accumulate to reach toxic levels. There are innu-
autosomal recessive disorder is characterized by extreme merable sources of lead in the environment, including
photosensitivity and a 2000-fold increased risk of skin aking paint, lead-contaminated dust and soil, pottery
cancer in sun-exposed skin. 2 glazes, traditional remedies, cosmetics, and wild game
contaminated by lead shot. Adults often encounter lead
No nio nizing Radiatio n. N onionizing radiation through occupational exposure. Lead and other metal
includes infrared light, ultrasound, microwaves, and smelters, miners, welders, storage battery workers, and
laser energy. 1 Unlike ionizing radiation, which can pottery makers are particularly at risk.2,7 Children are
directly break chemical bonds, nonionizing radiation exposed to lead through ingestion of peeling lead paint,
exerts its effects by causing vibration and rotation of by breathing dust from lead paint (e.g., during remodel-
atoms and molecules. All of this vibrational and rota- ing), playing in contaminated soil, or playing with toys
tional energy is eventually converted to thermal energy. or items made or decorated with lead.8,9 Factors that
Low-frequency nonionizing radiation is used widely in increase the risk of lead toxicity include preschool age,
radar, television, industrial operations (e.g., heating, low socioeconomic status, and living in housing built
welding, melting of metals, processing of wood and plas- before 1960.9
tic), household appliances (e.g., microwave ovens), and Lead is absorbed through the gastrointestinal tract or
medical applications (e.g., diathermy). Isolated cases the lungs into the blood. A de ciency in calcium, iron, or
of skin burns and thermal injury to deeper tissues have zinc increases lead absorption. In children, most lead is
occurred in industrial settings and from improperly used absorbed through the lungs. Although infants and chil-
household microwave ovens. Injury from these sources dren may have the same or a lower intake of lead as com-
is mainly thermal and, because of the deep penetration pared to adults, their absorption is greater. Also, the more
of infrared or microwave rays, tends to involve dermal permeable bloodbrain barrier of infants and children
and subcutaneous tissue injury. makes them highly susceptible to brain damage.2,7,9 Lead
crosses the placenta, exposing the fetus to levels of lead
that are comparable with those of the mother. M ost of the
Che m ical Injury
absorbed lead (80% to 85% ) is stored in bone (and teeth
Chemicals capable of damaging cells are everywhere of young children), 5% to 10% remains in the blood, and
around us. Pollutants in the air, water, and soil, such as the remainder accumulates in soft tissues.2 Although the
carbon monoxide, pesticides, and trace metals including half-life of lead is hours to days, bone serves as a reposi-
lead, are capable of tissue injury, as are certain chemi- tory from which blood levels are maintained. In a sense,
cals in foods. bone protects other tissues, but the slow turnover main-
Chemical agents can injure the cell membrane and tains blood levels for months to years.
other cell structures, block enzymatic pathways, coag- The toxicity of lead is related to its multiple biochem-
ulate cell proteins, and disrupt the osmotic and ionic ical effects.2,7 It has the ability to inactivate enzymes,
balance of the cell. Corrosive substances such as strong compete with calcium for incorporation into bone, and
acids and bases destroy cells as the substances come interfere with nerve transmission and brain develop-
into contact with the body. O ther chemicals may injure ment. The major targets of lead toxicity are the red blood
cells in the process of metabolism or elimination. For cells, the gastrointestinal tract, the kidneys, and the ner-
example, carbon tetrachloride (CCl4), a chemical used in vous system. Anemia is a cardinal sign of lead toxicity.

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C H A P T E R 2 Cellular Responses to Stress, Injury, and Aging 39

Lead competes with the enzymes required for hemo- sword sh. Fish concentrate mercury from sediment in
globin synthesis and with the membrane-associated the water. Because the developing brain is more suscep-
enzymes that prevent hemolysis of red blood cells. The tible to mercury-induced damage, it is recommended
life span of the red cell is decreased. The gastrointestinal that young children and pregnant and nursing women
tract is the main source of symptoms in the adult. This is avoid consumption of sh known to contain high mer-
characterized by lead colic, a severe and poorly local- cury content. Thimerosal is an ethyl mercurycontain-
ized form of acute abdominal pain. A lead line formed ing preservative that helps prevent microbial growth in
by precipitated lead sul te may appear along the gin- vaccines. Concern about potential adverse effects have
gival margins. The lead line is seldom seen in children. led to the creation of single-dose vials that eliminate the
The kidneys are the major route for excretion of lead. need for thimerosal.12 In the United States and Canada,
Lead can cause diffuse kidney damage, eventually lead- most vaccines are either free of thimerosal or contain
ing to renal failure. Even without overt signs of kidney only trace amounts.
damage, lead toxicity leads to hypertension.
In the nervous system, lead toxicity is characterized by Injury fro m Bio lo g ic Age nts
demyelination of cerebral and cerebellar white matter and
death of brain cells. When this occurs in early childhood, Biologic agents differ from other injurious agents in that
it can affect neurobehavioral development and result they are able to replicate and can continue to produce
in lower IQ levels and poorer classroom performance.9 their injurious effects (see Chapter 14). These agents
Demyelination of peripheral nerves may occur in adults. range from submicroscopic viruses to the larger para-
The most serious manifestation of lead poisoning is acute sites. Biologic agents injure cells by diverse mechanisms.
encephalopathy. It is manifested by persistent vomiting, Viruses enter the cell and incorporate its genetic mate-
ataxia, seizures, papilledema, impaired consciousness, rial into their cellular DN A, which then enables synthe-
and coma. Acute encephalopathy may manifest suddenly, sis of new viruses. Certain bacteria produce exotoxins
or it may be preceded by other signs of lead toxicity such that may interfere with cellular protein synthesis. O ther
as behavioral changes or abdominal complaints. bacteria, such as the gram-negative bacilli, release endo-
The threshold level at which lead causes subclinical toxins that cause cell injury and increased capillary
and clinical disturbances has been rede ned a number permeability.
of times over the past 50 years. At one time, a blood
level of 25 g/dL was considered safe. Recent research Injury fro m Nutritio nal Im balance s
suggests that even levels below 10 g/dL are associated N utritional excesses and nutritional de ciencies predis-
with declines in childrens IQ at 3 to 5 years of age.10,11 pose cells to injury. O besity and diets high in saturated
Approximately 99% of children are identi ed by fats are thought to predispose persons to atherosclerosis.
screening procedures, which are recommended for high- The body requires more than 60 organic and inorganic
risk populations based on the likelihood of lead expo- substances in amounts ranging from micrograms to
sure. A screening value greater than 10 g/dL requires grams. These nutrients include minerals, vitamins, cer-
repeat testing for a diagnosis and to determine the need tain fatty acids, and speci c amino acids. Dietary de -
for treatment. Treatment involves removal of the lead ciencies can occur because of a selective de ciency of a
source and, in cases of severe toxicity, administration of single nutrient. Iron-de ciency anemia, scurvy, beriberi,
a chelating agent. A public health team should evaluate and pellagra are examples of injury caused by a lack of
the source of lead because meticulous removal is needed. speci c vitamins or minerals. The protein and calorie
de ciencies that occur with starvation cause widespread
Me rcury Toxicity. M ercury has been used for industrial tissue damage.
and medical purposes for hundreds of years. M ercury
is toxic, and the hazards of mercury-associated occu-
pational and accidental exposures are well known. In
recent times, the primary concern of the general pub- M e c h a n is m s o f C e ll In ju ry
lic about the potential hazards of mercury has focused The mechanisms by which injurious agents cause cell
on exposure from eating certain sh, amalgams used in injury and death are complex. Some agents, such as heat,
dentistry, and vaccines. 12 M ercury is present in four pri- produce direct cell injury; other factors, such as genetic
mary forms: mercury vapor, inorganic divalent mercury, derangements, produce their effects indirectly through
methyl mercury, and ethyl mercury. 12 Depending on the metabolic disturbances and altered immune responses.
form of mercury exposure, toxicity involving the central There seem to be at least three major mechanisms
nervous system and kidney can occur. whereby most injurious agents exert their effects: free
In the case of dental llings, the concern involves radical formation, hypoxia and ATP depletion, and dis-
mercury vapor being released into the mouth. H owever, ruption of intracellular calcium homeostasis (Fig. 2-6).
the amount of mercury vapor released from llings
is very small. There is no clear evidence supporting Fre e Radical Injury
health risk from this type of exposure, and removal
of amalgams may temporarily increase blood levels of Cell injury in many circumstances involves the production
mercury.12 The main source of methyl mercury exposure of reactive chemical species known as free radicals.1,2,1315
is from consumption of long-lived sh, such as tuna and These circumstances include ischemia-reperfusion injury,

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40 U N I T 1 Cell and Tissue Function

In ju rio u s a g e n ts

Hypoxia /is che mia

O 2 , H2 O 2 , OH Ca ++

Intra ce llula r Ca
Fre e ra dica l forma tion

Ina ppropria te a ctiva tion of

e nzyme s tha t da ma ge ce ll
Oxida tion of ce ll
orga ne lle s , cytos ke le ton,
s tructure s a nd nucle a r Mitochondrion a nd ce ll me mbra ne s ;
a nd mitochondria l DNA
ha s te n ATP de ple tion; a nd
fra gme nt chroma tin

ATP de ple tion

Na +/K+-ATP a s e pump Ana e robic me ta bolis m Othe r e ffe cts

Influx Na a nd H2 O Glycoge n s tore s a nd De ta chme nt of ribos ome s ,

intra ce llula r pH de cre a s e d prote in s ynthe s is ,
a nd lipid de pos ition

Accumula tion of intra ce llula r fluids ,

dila tion of e ndopla s mic re ticulum,
incre a s e d me mbra ne pe rme a bility, FIG U RE 2 -6 . Me ch a n is m s o f ce ll in ju ry.
de cre a s e d mitochondria l function ATP, a d e n o s in e trip h o s p h a te .

chemical and radiation injury, toxicity from oxygen and that occurs when the generation of RO S exceeds the
other gases, cellular aging, responses to microbial infec- ability of the body to neutralize and eliminate RO S.
tions, and tissue injury caused by in ammation. O xidative stress can lead to oxidation of cell compo-
Free radicals are highly reactive chemical species with nents, activation of signal transduction pathways, DN A
an unpaired electron in the outer orbit (valence shell) of damage, and changes in gene expression. In addition to
the molecule. In the literature, the unpaired electron is focusing on nuclear DN A as a target of oxidative injury,
denoted by a dot, for example, N O . The unpaired elec- current studies are focusing on mitochondrial DN A as a
tron causes free radicals to be unstable and highly reac- target of oxidation and subsequent cause of mitochon-
tive, so that they react nonspeci cally with molecules in drial dysfunction.16
the vicinity. M oreover, free radicals can establish chain Although RO S and oxidative stress are clearly asso-
reactions consisting of many events that generate new ciated with cell and tissue damage, recent evidence
free radicals. In cells and tissues, free radicals react with suggests that RO S are not always acting in a random
proteins, lipids, and carbohydrates, thereby damaging and damaging manner. Current studies nd that RO S
cell membranes, inactivating enzymes, and damaging are also important signaling molecules that are used in
nucleic acids that make up DN A. healthy cells to regulate normal functions such as vas-
M any free radicals that are harmful in human physi- cular smooth muscle tone and vascular endothelial
ology are derived from oxygen. These reactive ox ygen growth factor (VEGF) signaling, and even function as
species (RO S) include free radicals, such as superoxide a preconditioning factor to protect cells from injury. 17
anion (O 2 ) and hydroxyl radical (O H ), as well as reac- Antioxidants are natural and synthetic molecules
tive oxygen-containing species that are not free radicals, that inhibit the reactions of ROS with biologic struc-
such as hydrogen peroxide (H 2 O 2). Reactive oxygen tures or that prevent the uncontrolled formation of RO S.
species are normal products of mitochondrial respira- Antioxidants include enzymatic and nonenzymatic com-
tion and energy metabolism, and are typically removed pounds. Enzymes known to function as antioxidants
by cellular antioxidative systems. Exogenous causes, include superoxide dismutase (SOD), catalase, glutathi-
including ionizing and UV radiation, can also cause RO S one peroxidase, and thioreductase. Superoxide dismutase
production in the body. O x idative stress is a condition forms hydrogen peroxide from superoxide. Catalase,

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C H A P T E R 2 Cellular Responses to Stress, Injury, and Aging 41

present in peroxisomes, catalyzes the reaction that forms H ypoxia causes a power failure in the cell, with wide-
water from hydrogen peroxide. N onenzymatic antioxi- spread effects on the cells structural and functional
dants include carotenes (e.g., vitamin A), tocopherols components. As oxygen tension in the cell falls, oxida-
(e.g., vitamin E), ascorbate (vitamin C), glutathione, and tive metabolism ceases, and the cell reverts to anaero-
avonoids, as well as micronutrients such as selenium and bic metabolism, using its limited glycogen stores in an
zinc.18 Nonenzymatic antioxidants often directly react attempt to maintain vital cell functions. Cellular pH falls
with oxidants to disarm them. For example, vitamin as lactic acid accumulates in the cell. This reduction in
C directly scavenges superoxide and hydroxyl radicals.19 pH can have adverse effects on intracellular structures
O xidative damage has been implicated in many and biochemical reactions. Low pH can alter cell mem-
diseases. M utations in the gene for SO D are associ- branes and cause chromatin clumping and cell volume
ated with amyotrophic lateral sclerosis (ALS; so-called changes.
L ou G ehrig disease). 20 O xidative stress is thought to An important effect of reduced ATP is acute cell swell-
have an important role in the development of can- ing caused by failure of the energy-dependent sodium/
cer.21 Reestablishment of blood ow following loss of potassium (N a +/K+)-adenosine triphosphatase (ATPase)
perfusion, as occurs during heart attack and stroke, is membrane pump, which extrudes sodium from and
associated with oxidative injury to vital organs. The returns potassium to the cell. With impaired function of
endothelial dysfunction that contributes to the devel- this pump, intracellular potassium levels decrease, and
opment, progression, and prognosis of cardiovascular sodium and water accumulate in the cell. The movement
diseases is thought to be caused in part by oxidative of water and ions into the cell is associated with dila-
stress. 22 In addition, oxidative stress has been associated tion of the endoplasmic reticulum, increased membrane
with age-related functional declines. 23 permeability, and decreased mitochondrial function. 2 To
a point, the cellular changes due to hypoxia are revers-
Hypoxic Ce ll Injury ible if oxygenation is restored. H owever, if the oxygen
supply is not restored there is continued loss of enzymes,
H ypoxia deprives the cell of oxygen and interrupts proteins, and ribonucleic acid through the hyperperme-
oxidative metabolism and the generation of ATP. The able cell membrane. Injury to the lysosomal membranes
actual time necessary to produce irreversible cell dam- results in the leakage of destructive lysosomal enzymes
age depends on the degree of oxygen deprivation and the into the cytoplasm and enzymatic digestion of cell com-
metabolic needs of the cell. Some cells, such as those in ponents. Leakage of intracellular enzymes through the
the heart, brain, and kidney, require large amounts of permeable cell membrane into the extracellular uid
oxygen to provide the energy to perform their functions. provides an important clinical indicator of cell injury
Brain cells, for example, begin to undergo permanent and death. These enzymes enter the blood and can be
damage after 4 to 6 minutes of oxygen deprivation. A measured by laboratory tests.
thin margin of time exists between reversible and irre-
versible cell damage. A classic study found that the epi- Im paire d Calcium Ho m e o s tas is
thelial cells of the proximal tubule of the kidney in the
rat could survive 20 but not 30 minutes of ischemia.24 Calcium functions as an important second messenger and
Recent work has identi ed a group of proteins called cytosolic signal for many cell responses. Various calcium-
hypox ia-inducible factors (H IFs). During hypoxic condi- binding proteins, such as troponin and calmodulin, act
tions, H IFs cause the expression of genes that stimulate as transducers for cytosolic calcium signaling. Calcium/
red blood cell formation, manufacture glycolytic enzymes calmodulindependent kinases indirectly mediate the
that produce ATP in the absence of oxygen, and increase effects of calcium on responses such as smooth muscle
angiogenesis25 (i.e., the formation of new blood vessels). contraction and glycogen breakdown. N ormally, intracel-
Hypoxia can result from an inadequate amount of oxy- lular calcium ion levels are kept extremely low compared
gen in the air, respiratory disease, ischemia (i.e., decreased with extracellular levels. These low intracellular levels
blood ow due to vasoconstriction or vascular obstruc- are maintained by energy-dependent membrane-associ-
tion), anemia, edema, or inability of the cells to use oxy- ated calcium/magnesium (Ca ++/M g++)-ATPase exchange
gen. Ischemia is characterized by impaired oxygen delivery systems2 and sequestration of calcium ions within organ-
and impaired removal of metabolic end products such as elles such as the mitochondria and smooth endoplasmic
lactic acid. In contrast to pure hypoxia, which depends reticulum. Ischemia and certain toxins lead to an increase
on the oxygen content of the blood and affects all cells in cytosolic calcium because of the increased in ux across
in the body, ischemia commonly depends on blood ow the cell membrane and the release of calcium from intra-
through limited numbers of blood vessels and produces cellular stores. The increased calcium level may inappro-
local tissue injury. In some cases of edema, the distance priately activate a number of enzymes with potentially
for diffusion of oxygen may become a limiting factor in damaging effects. These enzymes include phospholipases
the delivery of oxygen. In hypermetabolic states, the cells that can damage the cell membrane, proteases that dam-
may require more oxygen than can be supplied by normal age the cytoskeleton and membrane proteins, ATPases
respiratory function and oxygen transport. Hypoxia also that break down ATP and hasten its depletion, and endo-
serves as the ultimate cause of cell death in other injuries. nucleases that fragment chromatin. Although it is known
For example, physical factors such as a cold temperature that injured cells accumulate calcium, it is unknown
can cause severe constriction and impair blood ow. whether this is the ultimate cause of irreversible cell injury.

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42 U N I T 1 Cell and Tissue Function

Ce ll injury

Re ve rs ible injury, Apoptos is Ce ll de a th

ce ll re cove ry, a nd a nd
a nd re turn progra mme d ne cros is FIGURE 2 -7. Outcom es of cell injury: reversible cell injury,
to norma l function ce ll re mova l a p o p to s is a n d p ro g ra m m e d ce ll re m ova l, ce ll d e a th ,
a n d n e cro s is .

Re ve r s ib le C e ll In ju ry a n d C e ll D e a t h thereby controlling tissue regeneration. 26 Cells undergo-

ing apoptosis have characteristic morphologic features,
The mechanisms of cell injury can produce sublethal and as well as biochemical changes. As shown in Figure 2-8,
reversible cellular damage or lead to irreversible injury shrinking and condensation of the nucleus and cyto-
with cell destruction or death (Fig. 2-7). Cell destruction plasm occur. The chromatin aggregates at the nuclear
and removal usually involve one of two mechanisms: envelope, and DN A fragmentation occurs. Then, the cell
apoptosis, which is designed to remove injured or worn- becomes fragmented into multiple apoptotic bodies in a
out cells, or cell death or necrosis, which occurs in irre- manner that maintains the integrity of the plasma mem-
versibly damaged cells. brane and does not initiate in ammation. Changes in
the plasma membrane induce phagocytosis of the apop-
Re ve rs ible Ce ll Injury totic bodies by macrophages and other cells, thereby
Reversible cell injury, although impairing cell function, completing the degradation process.
does not result in cell death. Two patterns of revers- Apoptosis is thought to be responsible for several nor-
ible cell injury can be observed under the microscope: mal physiologic processes, including the programmed
cellular swelling and fatty change. Cellular swelling destruction of cells during embryonic development, hor-
occurs with impairment of the energy-dependent N a +/ mone-dependent involution of tissues, death of immune
K+-ATPase membrane pump, usually as the result of cells, cell death by cytotoxic T cells, and cell death in
hypoxic cell injury. proliferating cell populations. During embryogenesis, in
Fatty changes are linked to intracellular accumulation the development of a number of organs such as the heart,
of fat. When fatty changes occur, small vacuoles of fat which begins as a pulsating tube and is gradually modi-
disperse throughout the cytoplasm. The process is usu- ed to become a four-chambered pump, apoptotic cell
ally more ominous than cellular swelling, and although death allows for the next stage of organ development.
it is reversible, it usually indicates severe injury. These
fatty changes may occur because normal cells are pre-
sented with an increased fat load or because injured
cells are unable to metabolize the fat properly. In obese
persons, fatty in ltrates often occur within and between
the cells of the liver and heart because of an increased
fat load. Pathways for fat metabolism may be impaired A B
during cell injury, and fat may accumulate in the cell C
as production exceeds use and export. The liver, where
most fats are synthesized and metabolized, is particu-
larly susceptible to fatty change, but fatty changes may P ha gocytic ce ll
also occur in the kidney, the heart, and other organs.

Pro g ram m e d Ce ll De ath D

In most normal nontumor cells, the number of cells in E
tissues is regulated by balancing cell proliferation and F
cell death. Cell death occurs by necrosis or a form of FIG U RE 2 -8 . Ap o p to tic ce ll re m ova l. (A) S h rin kin g o f th e
programmed cell death called apoptosis. ce ll s tru ctu re s . (B, C) Co n d e n s a tio n a n d fra g m e n ta tio n o f th e
A poptosis, from the Greek apo for apart and ptosis n u cle a r ch ro m a tin . (D, E) Se p a ra tio n o f n u cle a r fra g m e n ts a n d
for fallen, means fallen apart. Apoptosis is a highly cyto p la s m ic o rga n e lle s in to a p o p to tic b o d ie s . (F) En g u lfm e n t o f
selective process that eliminates injured and aged cells, a p o p to tic fra g m e n ts b y p h a g o cytic ce ll.

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C H A P T E R 2 Cellular Responses to Stress, Injury, and Aging 43

It also separates the webbed ngers and toes of the Extrins ic

developing embryo. Apoptotic cell death occurs in the (de a th re ce ptorme dia te d)
hormone-dependent involution of endometrial cells dur- pa thwa y Intrins ic
TRAIL (mitochondria l-me dia te d)
ing the menstrual cycle and in the regression of breast pa thwa y
TNF Fa s L
tissue after weaning from breast-feeding. The control of
immune cell numbers and destruction of autoreactive Outs ide ce ll
Re ce ptor
T cells in the thymus have been credited to apoptosis.
Cytotoxic T cells and natural killer cells are thought to
destroy target cells by inducing apoptotic cell death.
Apoptosis is linked to many pathologic processes and
diseases. For example, interference with apoptosis is
known to be a mechanism that contributes to carcino- Ins ide ce ll
genesis.27 Apoptosis is also known to be involved in the FADD De a th doma in
cell death associated with viral infections, such as hepati- ROS
DNA da ma ge
tis B and C.27,28 Apoptosis may also be implicated in neu-
rodegenerative disorders such as ALS, Alzheimer disease, S e ne s ce nce
and Parkinson disease. H owever, the exact mechanisms Low ATP le ve l
involved in these diseases remains under investigation. Bid
Two basic pathways for apoptosis have been Ca s pa s e -9
described (Fig. 2-9). These are the extrinsic pathway,
which is death receptor dependent, and the intrinsic
pathway, which is death receptor independent. The Ba x
execution phase of both pathways is carried out by Mitochondrion
proteolytic enzymes called caspases (cysteine proteases
that cleave aspartate residues), which are present in the Cytochrome c
cell as procaspases and are activated by cleavage of an
inhibitory portion of their polypeptide chain. 2,29
The ex trinsic pathw ay involves extracellular signaling
proteins that bind to cell surface molecules called death
receptors and trigger apoptosis. The prototype death
Ca s pa s e -3 Ca s pa s e -8
receptors are tumor necrosis factor (TN F) receptor and (6 or 7)
the Fas ligand receptor. 29 Fas ligand may be expressed
on the surface of certain cells, such as cytotoxic T cells,
or appear in a soluble form. When Fas ligand binds to
its receptor, proteins congregate at the cytoplasmic end Apoptos is
of the Fas receptor to form a death-initiating complex.
The complex then converts procaspase-8 to caspase-8.
Caspase-8, in turn, activates a cascade of caspases that FIG U RE 2 -9 . Pa thways for a poptosis . The e xtrins ic pathway
execute the process of apoptosis. The end result includes is activated b y s ig n als su ch as TNF-rela te d ap o p to s is-in d u cin g
activation of endonucleases that cause fragmentation liga n d (TRAIL) a n d Fa s ligan d (Fas L) th a t, u p o n b in d in g to th e
of DN A and cell death. In addition to TN F and Fas Fas recepto r, form a d ea th -in ducin g com plex b y jo in in g th e
ligand, primary signaling molecules known to activate Fas-as so ciated d e ath d om a in (FADD) to th e d eath d om ain o f
the extrinsic pathway include TN F-related apoptosis- the Fas receptor. The in trin sic p ath wa y is activated b y signa ls,
su ch a s re a ctive oxyge n spe cie s (ROS) an d DNA da m a ge , which
inducing ligand (TRAIL); the cytokine interleukin-1 (IL-
in d u ce th e re le as e o f cyto ch ro m e c fro m m ito ch o n d ria in to
1); and lipopolysaccharide (LPS), the endotoxin found the cytopla sm . Both pa th ways activate caspa se s to exe cute
in the outer cell membrane of gram-negative bacteria. apoptos is , with activation of the pro -a poptotic prote ins Bid
The intrinsic pathw ay, or m itochondrion-induced and Ba x by caspa se -8 serving to bridge the tw o system s . ATP,
pathw ay, of apoptosis is activated by conditions such aden osine triphosp hate; DNA, d eoxyribonu cleic a cid; IL-1,
as DN A damage, RO S, hypoxia, decreased ATP lev- in te rleu kin -1; LPS , lip o p o lysa cch arid e; TNF, tu m o r n e cro sis facto r.
els, cellular senescence, and activation of the p53 pro-
tein by DN A damage. The intrinsic pathway is tightly including caspase-3. Caspase-3 activation is a com-
regulated to ensure that cells kill themselves only when mon step to both the extrinsic and intrinsic pathways.
appropriate. A major class of intracellular regulators of Activation of caspase-8 in the extrinsic pathway can
apoptosis is the Bcl-2 family of proteins. Some of these also lead to activation of pro-apoptotic proteins, such
proteins insert into the mitochondrial membrane open- as Bid and Bax, thereby bridging the two pathways for
ing channels through which proteins escape into the apoptosis. 2,29 While some members of the Bcl-2 family
cytoplasm.29 A crucial protein released from the mito- are pro-apoptotic, others are anti-apoptotic and inhibit
chondria is cytochrome c, a component of the mitochon- apoptosis by binding to pro-apoptotic proteins, either
drial electron transport chain (see Chapter 1). When on the mitochondrial membranes or in the cytoplasm.
released into the cytoplasm, cytochrome c binds to a Inhibitors of apoptosis are thought to contribute to
procaspase-activating protein that activates caspases, cancer and autoimmune diseases.2931 The Bcl-2 gene

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44 U N I T 1 Cell and Tissue Function

was rst identi ed in B-cell lymphoma, in which a

chromosomal translocation causes excessive produc-
tion of Bcl-2, giving the gene its name. 29 Excessive levels
of Bcl2 in the lymphocytes that carry the transloca-
tion promote the development of cancer by inhibiting
apoptosis. Similarly, mutation of the genes encoding
the tumor-suppressor protein p53 so that it no longer
suppresses apoptosis or cell cycle arrest in response to
DN A damage is implicated in a number of other cancers
(see Chapter 7). The therapeutic actions of certain drugs
may induce or facilitate apoptosis. Apoptosis continues
to be an active area of investigation to better understand
and treat a variety of diseases.

Ne cro s is
N ecrosis refers to cell death in an organ or tissue that is FIG U RE 2 -1 0 . Ga n g re n o u s to e s . (Bio m e d ica l Co m m u n ica tio n s
still part of a living person. 32 N ecrosis differs from apop- Gro u p , So u th e rn Illin o is Un ive rs ity Sch o o l o f Me d icin e ,
tosis in that it involves unregulated enzymatic digestion S p rin g e ld , IL.)
of cell components, loss of cell membrane integrity with
uncontrolled release of the products of cell death into
the extracellular space, and initiation of the in amma- demarcation) between the dead tissue of the gangrenous
tory response.32 In contrast to apoptosis, which func- area and the healthy tissue (Fig. 2-10). Dry gangrene
tions in removing cells so new cells can replace them, usually results from interference with arterial blood sup-
necrosis often interferes with cell replacement and tissue ply to a part without interference with venous return
regeneration. and is a form of coagulation necrosis.
With necrosis, there are marked changes in the appear- In moist or wet gangrene, the area is cold, swollen,
ance of the cytoplasmic contents and the nucleus. These and pulseless. The skin is moist, black, and under ten-
changes often are not visible, even under a microscope, sion. Blebs form on the surface, liquefaction occurs, and
for hours after cell death. The dissolution of the necrotic a foul odor is caused by bacterial action. There is no line
cell or tissue can follow several paths. L iquefaction of demarcation between the normal and diseased tissues,
necrosis occurs when some of the cells die but their and the spread of tissue damage is rapid. Systemic symp-
catalytic enzymes are not destroyed. An example of liq- toms are usually severe, and death may occur unless
uefaction necrosis is the softening of the center of an the condition can be arrested. M oist or wet gangrene
abscess with discharge of its contents. During coagula- primarily results from interference with venous return
tion necrosis, acidosis develops and denatures the enzy- from the part. Bacterial invasion plays an important role
matic and structural proteins of the cell. This type of in the development of wet gangrene and is responsible
necrosis is characteristic of hypoxic injury and is seen for many of its prominent symptoms. Dry gangrene is
in infarcted areas. Infarction (i.e., tissue death) occurs con ned almost exclusively to the extremities, but moist
when an artery supplying an organ or part of the body gangrene may affect the internal organs or the extremi-
becomes occluded and no other source of blood supply ties. If bacteria invade the necrotic tissue, dry gangrene
exists. As a rule, the shape of the infarction is conical may be converted to wet gangrene.
and corresponds to the distribution of the artery and its G as gangrene is a special type of gangrene that results
branches. An artery may be occluded by an embolus, a from infection of devitalized tissues by one of several
thrombus, disease of the arterial wall, or pressure from Clostridium bacteria, most commonly Clostridium per-
outside the vessel. fringens. These anaerobic and spore-forming organ-
Caseous necrosis is a distinctive form of coagula- isms are widespread in nature, particularly in soil; gas
tion necrosis in which the dead cells persist inde nitely gangrene is prone to occur in trauma and compound
as soft, cheese-like debris.1 It is most commonly found fractures in which dirt and debris are embedded. Some
in the center of tuberculosis granulomas, or tubercles, species have been isolated in the stomach, gallblad-
and is thought to result from immune mechanisms (see der, intestine, vagina, and skin of healthy persons. The
Chapter 22). bacteria produce toxins that dissolve cell membranes,
The term gangrene is applied when a considerable causing death of muscle cells, massive spreading edema,
mass of tissue undergoes necrosis. Gangrene may be clas- hemolysis of red blood cells, hemolytic anemia, hemo-
si ed as dry or moist. In dry gangrene, the part becomes globinuria, and renal failure. 33 Characteristic of this dis-
dry and shrinks, the skin wrinkles, and its color changes order are the bubbles of hydrogen sul de gas that form
to dark brown or black. The spread of dry gangrene is in the muscle. Gas gangrene is a serious and potentially
slow, and its symptoms are not as marked as those of fatal disease. Antibiotics are used to treat the infection
wet gangrene. The irritation caused by the dead tissue and surgical methods are used to remove the infected tis-
produces a line of in ammatory reaction (i.e., line of sue. Amputation may be required to prevent spreading

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C H A P T E R 2 Cellular Responses to Stress, Injury, and Aging 45

infection involving a limb. H yperbaric oxygen therapy maintained by an enzyme called telom erase, which is
has been used, but clinical data supporting its ef cacy present in low levels in stem cells, but is usually absent
has not been rigorously assessed. in most adult cells. Therefore, as cells age, their telo-
meres become shorter and they lose their ability to rep-
licate and replace damaged or senescent cells. M oreover,
C e llu la r Ag in g oxidative stress induces single-stranded damage to
telomeric DN A, and this defect cannot be repaired in
Aging is a complex natural process in which there are telomeres. In theory, such mechanisms could also pro-
physiologic and structural alterations in almost all organ vide a safeguard against uncontrolled cell proliferation
systems.1,2,3438 Even in the absence of disease, beginning of abnormal cells. It has been shown that telomerase is
in the fourth decade of life, there is a progressive decline reactivated and telomeres are not shortened in immortal
in muscle strength, cardiac reserve, vital capacity, nerve cancer cells, suggesting that telomere elongation may be
conduction time, and glomerular ltration rate. Although important in tumor formation.
the biologic basis of aging is poorly understood, there is
general consensus that its elucidation should be sought
at the cellular level. M any cell functions decline with Ge ne tic In ue nce s
age. O xidative phosphorylation by the mitochondria is There is ongoing interest in genes that determine longev-
reduced, as is synthesis of nucleic acids and transcription ity. Longevity genes have been found in fruit ies and
factors, cell receptors, and cell proteins. roundworms, organisms that have attracted consider-
A number of theories have been proposed to explain able attention from scientists because of their short life
the cause of aging. The main theories are based on sci- span and their well-characterized genomes. O ne exam-
enti c observations at the molecular, cellular, organ, ple is the mutation of the Indy (Im N ot Dead Yet) gene
and system levels. In general, these theories can be in the fruit y, which can double the length of its life.35
divided into either programmed or error theories. The Scientists have also found genetic clues to the aging pro-
program m ed theories propose that the changes that cess in the tiny roundworm, Caenorhabditis elegans. By
occur with aging are genetically programmed, whereas altering one of its daf-2 genes, which codes for a pro-
the dam age or error theories maintain that the changes tein that is similar to insulin and insulin growth factor
result from an accumulation of random events or envi- (IGF)-1 receptors found in humans, researchers can
ronmental agents or in uences that are associated with substantially extend the longevity of these worms.1,35
DN A damage. 3539 Evidence suggests that the process of Pathways related to the daf-2 gene, for example, may be
aging and longevity is multifaceted, with both genetic responsible for relationships between caloric restriction
and environmental factors playing a role. In animal and prolonged life span in rodents and other animals.
studies, genetics accounted for less than 35% of the Whether human counterparts of genes found in these
effects of aging, whereas environmental in uences laboratory organisms exist and whether they have simi-
accounted for over 65% . 36 In humans, long life appears lar effects remain an ongoing area of inquiry.
to have a stronger genetic basis, which explains why H owever, many genes that are associated with
centenarians and near centenarians tend to cluster in human life span are not intrinsically longevity genes,
families.40 per se. For example, because mutations in the tumor-
suppressor genes BRAC1 and BRAC2 increase mortal-
ity associated with breast and ovarian cancer, they are
Re plicative S e ne s ce nce
rare among long-lived women.40 Conversely, genes that
Replicative senescence implies that cells have a limited reduce the risk of atherosclerosis may be more common
capacity for replication. At the cellular level, H ay ick in long-lived individuals. Genetic studies of biologic
and M oorhead observed more than 40 years ago that aging have also explored the involvement of variants of
cultured human broblasts have a limited ability to rep- genes encoding apolipoproteins (proteins that bind lip-
licate (approximately 50 population doublings) and then ids for transport in the circulatory system), in particular,
die.41 Before achieving this maximum, they slow their the APO E gene encoding the synthesis of apolipoprotein
rate of division and manifest identi able and predictable E. The presence of the variant apoE4 is associated with
morphologic changes characteristic of senescent cells. an increased incidence of cardiovascular and neurode-
O ne explanation of replicative senescence is related generative diseases, thereby shortening life span. 37,41
to the length of the outermost regions of each chro-
mosome, called telom eres, that contain short repeat Accum ulatio n o f Enviro nm e ntal and
sequences of DN A bases.1,2,35 During mitosis, the molec- Ge ne tic Dam age
ular machinery that replicates DN A cannot copy the
extreme ends of the chromosome. Thus, with each cell In addition to the importance of timing and a genetic
division, a small segment of telomeric DN A is lost. O ver clock, cellular life span may be determined by a balance
time, it is theorized that as the telomeres become pro- between cellular damage resulting from metabolic events
gressively shorter, the DN A at the ends of the chromo- occurring within the cell and molecular responses that
somes cannot be protected, resulting in inhibition of cell repair the damage. The damage eventually accumulates
replication. The lengths of the telomeres are normally to a level suf cient to result in the physiologic decline

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46 U N I T 1 Cell and Tissue Function

associated with aging. The most prominent example of

the damage theory is the somatic mutation theory of
aging, which states that the longevity and function of
cells in various tissues of the body are determined by the
double-stranded DN A molecule and its speci c repair
enzymes. Deoxyribonucleic acid undergoes continuous
change in response to both exogenous agents and intrin-
sic processes. It has been suggested that aging results
from conditions that produce mutations in DN A or de -
cits in DN A repair mechanisms.
The oxidative free radical explanation of aging is
an error theory in which aging is thought to result
partially from oxidative stress and the effects of free
radical damage. The major by-products of oxidative
metabolism include superoxides that react with DN A,
ribonucleic acid, proteins, and lipids, leading to cellu-
lar damage and aging. Blood glucose is another suspect
in cellular deterioration. In a process called nonenzy-
m atic glycation, glucose molecules attach to proteins,
setting in motion a chain of chemical reactions that
ends with proteins binding together or cross-linking,
thus altering their structure and function. Investigators
hypothesize that glycation and oxidation are interde-
pendent, since free radicals and cross-links seem to
accelerate the formation of one another. Cross-links,
also known as advanced glycation end products
(A G Es), tend to stiffen tissues and cause some of the
deterioration associated with aging. 2,35 For example, FIG U RE 2 -11. A 5-ye a r-g irl w ith p ro g e ria . (Fro m Na tio n a l
Hu m a n Ge n o m e Re s e a rch In s titu te , Na tio n a l In s titu te s
AGEs may help trap low-density cholesterol in arte-
o f He a lth .)
rial walls and thus contribute to atherosclerosis. They
also have been linked to cataract formation, reduced
kidney function, and neurologic disorders such as
Alzheimer disease.

Syndro m e s o f Pre m ature Ag ing S U M M A R Y C O N C EP TS

The syndromes of premature aging, or progeria, rep-
resent a range of phenotypes seen in usual aging, but Ce ll in ju ry ca n b e ca u s e d b y a n u m b e r o f a g e n ts ,
with much earlier ages of onset and more rapid rates of
in clu d in g p hys ica l a g e n ts , ch e m ica ls , b io lo g ic
progression. 1 H utchinson-Gilford progeria syndrome is
a g e n ts , a n d n u tritio n a l fa cto rs .
a rare fatal genetic disorder characterized by acceler-
ated aging in children. 42 The disorder is caused by a Am o n g th e p hys ica l a g e n ts th a t g e n e ra te ce ll
mutation in the L M N A gene, which codes for a pre- in ju ry a re m e ch a n ica l fo rce s th a t p ro d u ce tis s u e
cursor of lamin Aa scaffolding protein that lines the tra u m a , e xtre m e s o f te m p e ra tu re , a n d e le ctrica l
nucleus. The mutant gene leads to abnormal nuclear fo rce s . Io n izin g ra d ia tio n ca n d ire ctly b re a k
structure and altered gene regulation and DN A replica- ch e m ica l b o n d s , w h e re a s n o n io n izin g ra d ia tio n
tion. Although they are born looking healthy, children
e xe rts its h a rm fu l e ffe cts b y ca u s in g vib ra tio n
with the disorder begin to display many characteristics
a n d ro ta tio n o f a to m s a n d m o le cu le s . Ch e m ica l
of accelerated aging at around 18 to 24 months of age.
Progeria signs include growth failure, loss of body fat a g e n ts ca n b lo ck e n zym a tic p a th wa ys , ca u s e
and hair, aged-looking skin, cataracts, and coronary co a g u la tio n o f tis s u e s , o r d is ru p t th e o s m o tic o r
artery disease and stroke (Fig. 2-11). Death occurs at io n ic b a la n ce o f th e ce ll. Bio lo g ic a g e n ts d iffe r
an early age of atherosclerotic heart disease (average fro m o th e r in ju rio u s a g e n ts in th a t th e y a re a b le
age 13 years). to re p lica te a n d co n tin u e to p ro d u ce in ju ry.
O ther progeroid syndromes include Werner syn- Am o n g th e n u tritio n a l fa cto rs th a t co n trib u te to
drome, also known as adult progeria, which does not ce ll in ju ry a re e xce s s e s a n d d e cie n cie s o f to ta l
have an onset until the late teens, with a life span into e n e rg y, a s w e ll a s in d ivid u a l n u trie n ts .
the 40s and 50s.1 The gene responsible for the disor-
der has been localized to chromosome 8 and appears to In ju rio u s a g e n ts e xe rt th e ir e ffe cts la rg e ly th ro u g h
code for an enzyme involved in unwinding DN A, a pro- g e n e ra tio n o f re a ctive oxyg e n s p e cie s (ROS )
cess that is necessary for DN A repair and replication.

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C H A P T E R 2 Cellular Responses to Stress, Injury, and Aging 47

a n d fre e ra d ica ls , p ro m o tio n o f ce ll hyp oxia , 3. People who have had a heart attack may experience
o r im p a ire d re g u la tio n o f in tra ce llu la r ca lciu m additional damage once blood ow has been restored,
le ve ls . Fre e ra d ica ls a re a n im p o rta n t ca u s e o f ce ll a phenomenon referred to as reperfusion injury.
in ju ry in hyp oxia a n d a fte r e xp o s u re to ra d ia tio n A. What is the proposed mechanism underlying
a n d ce rta in ch e m ica l a g e n ts . La ck o f oxyg e n , reperfusion injury?
w h ich u n d e rlie s th e p a th o g e n e s is o f ce ll in ju ry in B. What factors might in uence this mechanism?
hyp oxia a n d is ch e m ic, ca n re s u lt fro m in a d e q u a te
o xyg e n in th e a ir, ca rd io p u lm o n a ry d is e a s e , 4. Every day blood cells in our body become senescent
ca rd io re s p ira to ry d is e a s e , a n e m ia , o r th e in a b ility and die without producing signs of in ammation,
yet massive injury or destruction of tissue, such
o f th e ce lls to u s e oxyg e n . In cre a s e d in tra ce llu la r
as occurs with a heart attack, produces signi cant
ca lciu m a ctiva te s a n u m b e r o f e n zym e s w ith
signs of in ammation.
p o te n tia lly d a m a g in g e ffe cts .
A. Explain.
In ju rio u s a g e n ts m a y p ro d u ce s u b le th a l a n d
re ve rs ib le ce llu la r d a m a g e o r m a y le a d to
irre ve rs ib le ce ll in ju ry a n d d e a th . Ce ll d e a th ca n
invo lve tw o m e ch a n is m s : a p o p to s is o r n e cro s is . REFEREN CES
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27. Vermeulen K, Van Bockstaele DR, Berneman Z N . Apoptosis: 41. Vijg J, Suh Y. Genetics of longevity and aging. A nnu R ev M ed.
mechanisms and relevance in cancer. A nn H em atol. 2005;56:193212.
2005;84:627639. 42. Warner H H . Research on H utchinson-Gilford progeria
28. Cruise M W, Lukens JR, N guyen AP, et al. Fas ligand is syndrome. J G erantol. 2008;63A(3):775786.
responsible for CXCR3 chemokine induction in CD4+ T cell-
dependent liver damage. J Im m unol. 2006;176:62356244.
29. Alberts B, Johnson A, Lewis L, et al. M olecular Biology of the
Cell. 5th ed. N ew York, N Y: Garland Press; 2008:11151129. Po rth Es s e ntia ls Re s ou rces
30. M alhi H , Gores GJ, Lemasters JJ. Apoptosis and necrosis in Explore the se additional re source s to e nhance le arning
the liver: a tale of two deaths? H epatology. 2006;43(2 suppl for this chapte r:
1):S31S44. NCLEX-Style Que stions and Othe r Re source s
31. Dorner T, Lipsky PE. Signalling pathways in B cells: implications for on , http://the Point.lw w.com/PorthEsse ntials4e
autoimmunity. Curr Top Microbiol Immunol. 2006;305:213240.
Study Guide for Esse ntials of Pathophysiology
32. Proskuryakov SY, Konoplyannikov AG, Gabai VL. N ecrosis:
a speci c form of programmed cell death. Ex p Cell R es. Adaptive Le arning | Powe re d by Pre pU, http://the point.lw w.com/
2003;283:116. pre pu

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Genera l Fea tures of In a mma tion
Cells of In a mma tion
Endothelia l Cells
Pla telets
Cell Adhesion Molecules
C h a p t e r
Acute In a mma tion
Sta ges of Acute In a mma tion In a m m a t io n ,
t h e In a m m a t o r y
Va scula r Sta ge
Cellula r Sta ge
In a mma tory Media tors
Pla sma -Derived Media tors
Cell-Derived Media tors
Re s p o n s e , a n d
Loca l Ma nifesta tions
Resolution Fe v e r
Chronic In a mma tion
Ca uses of Chronic In a mma tion
G ra nuloma tous In a mma tion
Systemic Ma nifesta tions of In a mma tion
Acute-Pha se Response
Acute-Pha se Proteins
I n ammation is a complex nonspeci c response to tis-
sue injury intended to minimize the effects of injury or
infection, remove the damaged tissue, generate new tis-
W hite Blood Cell Response sue, and facilitate healing. As part of the innate immune
Systemic In a mma tory Response system, in ammation dilutes, destroys, and gets rid of
Fever damaged or necrotic tissues and foreign agents, such
Body Tempera ture Regula tion as microbes. Although rst described over 2000 years
The Febrile Response
ago, the in ammatory response has been the subject of
intense research during the past several decades. As a
Ma nifesta tions of Fever
result, it is now recognized as playing a key role in both
Ma na gement of Fever the contributing factors and consequences of numer-
Fever in Children ous diseases and altered health states including, but not
Fever in the Elderly limited to, atherosclerosis, obesity and diabetes, many
types of cancers, stroke, bronchial asthma, rheumatoid
arthritis, and certain dementias, including Alzheimer
The discussion in this chapter is divided into four
sections: (1) the general features of in ammation, (2)
acute in ammation, (3) chronic in ammation, and (4)
systemic manifestations of in ammation, including
fever. The innate and adaptive immune responses that
are closely intertwined with the in ammatory response
are discussed in Chapter 15.

G e n e r a l Fe a t u r e s o f
In a m m a t io n
In ammation is the reaction of vascularized tissues to
cell injury or death. It is characterized by the production
and release of in ammatory mediators and the move-
ment of uid and leukocytes from the vasculature into
the extravascular tissues. 14 In ammatory conditions
are commonly named by adding the suf x -itis to the
affected organ or system. For example, appendicitis
refers to in ammation of the appendix, pericarditis to
in ammation of the pericardium, and neuritis to in am-
mation of the nerve.


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50 U N I T 1 Cell and Tissue Function

In ammation can be acute or chronic. 1,2 A cute vasoconstrictors that regulate blood ow. Endothelial
in am m ation is triggered by noxious stimuli, such as cells are also key players in the in ammatory response.
infection or tissue injury, is rapid in onset (typically As such, they provide a selective permeability barrier
minutes), and is of relatively short duration, last- to exogenous (microbial) and endogenous in am-
ing from a few minutes to several days. It is charac- matory stimuli; regulate leukocyte extravasation by
terized by the exudation of uid and plasma proteins expression of adhesion molecules and receptor acti-
and emigration of leukocytes. Chronic in am m ation is vation; contribute to the regulation and modulation
of a longer duration, lasting for days to years, and is of immune responses through synthesis and release
often associated with the proliferation of blood vessels of in ammatory mediators; and regulate immune
(angiogenesis), tissue necrosis, and brosis (scarring). cell proliferation through secretion of hematopoietic
Acute and chronic in ammation may coexist, with epi- colony-stimulating factors (CSFs). Endothelial cells
sodes of acute in ammation being superimposed on also participate in the repair process that accompa-
chronic in ammation. nies in ammation through the production of growth
factors that stimulate angiogenesis and extracellular
matrix synthesis.
C e lls o f In a m m a t io n
M any cells and tissue components are involved in the Plate le ts
in ammatory process, including the endothelial cells
Platelets or thrombocytes are small, membrane-bound
that line blood vessels and form capillaries, circulat-
disks circulating in the blood that play an active role
ing platelets and leukocytes, cells in the connective tis-
in normal hemostasis (see Chapter 12). Activated
sue (mast cells, broblasts, tissue macrophages), and
platelets also release a number of potent in ammatory
components of the extracellular matrix (Fig. 3-1). 13
mediators, thereby increasing vascular permeability
The principal leukocytes in acute in ammation are
and altering the chemotactic, adhesive, and proteolytic
neutrophils, whereas macrophages, lymphocytes,
properties of the endothelial cells. 6,7 When a platelet
eosinophils, and mast cells predominate in chronic
undergoes activation, over 300 proteins are released.
While the functions of only a relatively small proportion
of these proteins have been fully elucidated, it appears
Endo the lial Ce lls
that many help mediate in ammation. 6 The associa-
Endothelial cells, which make up the single-cell-thick tion between the platelet and in ammatory diseases
linings of blood vessels, help to separate the intravas- is highlighted by the number of in ammatory disease
cular and extravascular spaces. 1,2,5 They normally have processes (e.g., atherosclerosis, migraine headaches,
a nonthrombogenic surface and produce agents that systemic lupus erythematosus) shown to be associated
maintain vessel patency, as well as vasodilators and with platelet activation. 6

Endothe lia l ce lls

Ba s ophil Lymphocyte Ne utrophil

Eos inophil P la te le ts Monocyte

Fibrobla s t

Ma s t ce ll Ma cropha ge
Ela s tin

FIG U RE 3 -1. Ce lls invo lve d in th e

Colla ge n fibe rs P rote oglyca n fila me nts in a m m a to ry p ro ce s s .

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C H A P T E R 3 In ammation, the In ammatory Response, and Fever 51

Le uko cyte s Eo s ino phils . Eosinophils account for 2% to 3% of cir-

culating leukocytes and are recruited to tissues in a simi-
Leukocytes or white blood cells are the major cellular lar way as the neutrophils. Their appearance at the site of
components of the in ammatory response. They include in ammation occurs 2 to 3 hours after the neutrophils.
the granulocytes (neutrophils, eosinophils, and baso- This is, in part, because of their slower mobility and
phils), which contain speci c cytoplasmic granules and a comparatively slower reaction to chemotactic stimuli.
multilobed nucleus, and the agranulocytes (monocytes/ The granules of eosinophils, which stain pink with
macrophages and lymphocytes), which lack cytoplasmic the acid dye eosin, contain a protein that is highly toxic
granules and have a single nucleus. to large parasitic worms that cannot be phagocytized.
Eosinophils also play an important role in allergic reac-
Ne utro phils . N eutrophils are the most numerous leu- tions by controlling the release of speci c chemical
kocytes in the circulating blood, accounting for 60% mediators. They interact with basophils and are promi-
to 70% of all white blood cells. These leukocytes have nent in allergic reactions such as hay fever and bronchial
nuclei that are divided into three to ve lobes; therefore, asthma. Eosinophils have a longer life span than neutro-
they often are referred to as polym orphonuclear neutro- phils and therefore are present in chronic in ammation.
phils (PM N s). Because of their ability to form pseudo-
pods used in ameboid movement, neutrophils are highly Bas o phils and Mas t Ce lls . Basophils are granulocytes
mobile, and are the rst cells to appear at the site of with granules that stain blue with a basic dye. Although
acute in ammation, usually arriving within 90 minutes they account for less than 1% of the circulating leuko-
of injury (Fig. 3-2A). N eutrophils are scavenger cells cytes, they are important participants in in ammatory
capable of engul ng bacteria and other cellular debris reactions and are most prominent in allergic reactions
through phagocytosis. Their cytoplasmic granules, mediated by immunoglobulin E (IgE). Binding of IgE
which resist staining and remain a neutral color, con- triggers release of histamine and vasoactive agents from
tain enzymes and other antibacterial substances that are the basophil granules.
used in destroying and degrading engulfed microbes and M ast cells derive from the same hematopoietic stem
dead tissue.3,8,9 N eutrophils also have oxygen-dependent cells as basophils but do not develop until they leave the
metabolic pathways that generate toxic reactive oxy- circulation and lodge in tissue sites. They are particularly
gen (e.g., hydrogen peroxide) and nitrogen (e.g., nitric prevalent along mucosal surfaces of the lung, gastroin-
oxide) species that aid in the destruction of engulfed testinal tract, and dermis of the skin.2,10 This distribution
pathogens. N eutrophils have a short life span. They die places them in a sentinel position between environmental
by apoptosis and disappear within 24 to 48 hours after antigens and the host for a variety of acute and chronic
entering the site of in ammation. in ammatory conditions. 2 Activation of mast cells


FIG U RE 3 -2 . In a m m a to ry ce lls o f a cu te a n d ch ro n ic in a m m a tio n . (A) Acu te in a m m a tio n w ith

d e n s e ly p a cke d p o lym o rp h o n u cle a r n e u tro p h ils w ith m u ltilo b e d n u cle u s (a rro w s ). (B) Ch ro n ic
in a m m a tio n w ith lym p h o cyte s , p la s m a ce lls (a rro w s ), a n d a fe w m a cro p h a g e s . (Fro m Mu rp hy HS .
In a m m a tio n . In : Ru b in R, S tra ye r DS , e d s . Ru b ins Pa th o lo g y: Clin ico p a th o lo g ic Fo u n d a tio n s o f
Me d icin e . 5th e d . Ph ila d e lp h ia , PA: Wo lte rs Klu w e r He a lth /Lip p in co tt Willia m s & Wilkin s ; 20 08:39.)

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52 U N I T 1 Cell and Tissue Function

results in release of the preformed contents of their gran- perpetuating cycle of cellular responses that fuel and
ules (e.g., histamine, proteases, cytokines such as tumor sustain chronic in ammation.
necrosis factor- [TN F-] and interleukin-16 [IL-16], Plasma cells develop from B lymphocytes that have
growth factors such as vascular endothelial growth fac- become activated after encountering an antigen and
tor [VEGF]) and synthesis of lipid mediators derived receiving T cell help. In the in ammatory site, they
from cell membrane precursors (arachidonic acid metab- produce antibodies directed against persistent anti-
olites, such as prostaglandins, and platelet-activating gens and altered tissue components. In some intense,
factor). Finally, the release of mast cell contents stimu- chronic in ammatory reactions, plasma cells and other
lates cytokine and chemokine synthesis by other in am- lymphocytes may accumulate to form geminal centers
matory cells such as monocytes and macrophages. that resemble lymph nodes. 2 This pattern of lympho-
cyte accumulation, with formation of germinal centers,
Mo no cyte / Macro phage s . M onocytes constitute 3% is often seen in the in amed synovium of persons with
to 8% of the white blood cell count. They have a single long-standing rheumatoid arthritis.
kidney-shaped nucleus and are the largest of the circu-
lating leukocytes. The half-life of circulating monocytes
is about a day, after which they begin to migrate to C e ll Ad h e s io n M o le c u le s
the site of injury and mature into larger macrophages,
which have a longer half-life and greater phagocytic Several families of cell adhesion molecules, including
ability than do blood monocytes. Circulating mono- selectins, integrins, and the immunoglobulin superfam-
cytes have been linked to a number of in ammatory ily, are involved in leukocyte recruitment and traf cking
disorders, particularly atherosclerosis, in which they are (see Chapter 1). 8,11,12 The selectins are a family of three
transformed into macrophages that accumulate in ath- closely related proteins (E-selectin, L-selectin, P-selectin)
erosclerotic plaques and turn into lipid-laden foam cells that differ in their cellular distribution but all function in
(see Chapter 18). adhesion of leukocytes or platelets to endothelial cells.
M onocyte/macrophages produce potent vasoactive The integrins consist of different types of structurally
mediators including prostaglandins and leukotrienes, similar transmembrane receptor proteins that function
platelet-activating factor (PAF), in ammatory cyto- as heterodimers to promote cell-to-cell and cellto
kines, and growth factors that promote regeneration extracellular matrix interactions. The name integrin
of tissues. 8,9 As their name implies, macrophages are derives from the hypothesis that they integrate the sig-
capable of phagocytosis and are active in bacterial killing. nals of extracellular ligands with cytoskeleton-dependent
They engulf larger and greater quantities of foreign motility, shape change, and phagocytic responses of
material than the neutrophils, and their circulating life immune cells. Cell adhesion m olecules of the immuno-
span is three to four times longer than that of any gran- globulin superfamily include intercellular adhesion and
ulocyte. These longer-lived phagocytes help to destroy vascular adhesion molecules, which interact with integ-
the causative agent, aid in the signaling processes of rins on leukocytes to mediate their recruitment.
immunity, serve to resolve the in ammatory process, The importance of the leukocyte adhesion molecules
and contribute to initiation of the healing processes. is demonstrated in persons with an inherited disorder
M acrophages are especially important in maintaining called leuk ocyte adhesion de ciency (L A D ) type I, in
chronic in ammation. which de ciency of a member of the integrin superfam-
ily leads to severe leukocytosis and recurrent infections.
Lym pho cyte s and Plas m a Ce lls . Lymphocytes are A similar de ciency is seen in individuals with impaired
the smallest of the leukocytes and have a thin rim of expression of a member of the selectin superfamily and
cytoplasm surrounded by a deeply staining nucleus has been labeled L A D type 2.8 There is also evidence that
(Fig. 3-2B). They participate in immune-mediated excessive expression of cell adhesion molecules or their
in ammation caused by infectious agents as well as receptors contributes to the pathogenesis of some chronic
nonimmune-mediated in ammation associated with in ammatory diseases such as rheumatoid arthritis.
cell injury and death. Both T and B lymphocytes (T and
B cells) migrate into in ammatory sites using some of the
same adhesion molecules and chemokines that recruit S U M M A R Y C O N C EP TS
neutrophils and other leukocytes (discussed in Chapter 15).
Lymphocytes and macrophages communicate in a bidi-
rectional way, and these interactions play an important In a m m a tio n is th e b o d y's re s p o n s e to in ju ry
role in chronic in ammation. M acrophages display a n d is ch a ra cte rize d b y th e e la b o ra tio n o f
antigen to T cells, express membrane molecules called ch e m ica l m e d ia to rs a n d m o ve m e n t o f u id a n d
costimulators (meaning that their response requires the le u ko cyte s fro m th e va s cu la r co m p a rtm e n t in to
action of two signaling molecules), and produce cyto- th e e xtra va s cu la r tis s u e s p a ce .
kines that stimulate T-cell responses. 2 Activated T cells,
Th e re a re tw o typ e s o f in a m m a tio n : a cu te
in turn, produce cytokines that activate macrophages,
increasing antigen presentation and further cytokine in a m m a tio n , w h ich is o f s h o rt d u ra tio n a n d
production. (Cytokines and other in ammatory media- ch a ra cte rize d b y th e e xu d a tio n o f u id a n d
tors are discussed later in this chapter.) The result is a

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C H A P T E R 3 In ammation, the In ammatory Response, and Fever 53

injury and are characterized by vasodilation and changes

p la s m a p ro te in s , a n d ch ro n ic in a m m a tio n , in blood ow followed by increased vascular permeabil-
w h ich is a s s o cia te d w ith a n g io g e n e s is , tis s u e ity and leakage of protein-rich uid into the extravascular
n e cro s is , a n d b ro s is (s ca rrin g ). tissue space.1,2
Vasodilation, which is one of the earliest manifesta-
Ma ny ce lls a n d tis s u e co m p o n e n ts co n trib u te tions of in ammation, follows a transient constriction
to th e in a m m a to ry re s p o n s e , in clu d in g th e of the arterioles, lasting a few seconds. Dilation begins
e n d o th e lia l ce lls th a t fo rm ca p illa rie s a n d lin e in the arterioles and opens capillary beds in the area. As
b lo o d ve s s e ls , circu la tin g p la te le ts a n d w h ite a result, the area becomes congested, causing the redness
b lo o d ce lls , ce lls in co n n e ctive tis s u e , a n d (erythema) and warmth associated with acute in am-
co m p o n e n ts o f th e e xtra ce llu la r m a trix. mation. Vasodilation is induced by the action of several
mediators, most notably histamine and nitric oxide.
Vasodilation is quickly followed by increased perme-
ability of the microvasculature, with the outpouring of a
protein-rich uid (exudate) into the extravascular spaces.
Ac u t e In a m m a t io n The loss of uid results in an increased concentration of
blood constituents (red blood cells, leukocytes, platelets,
Acute in ammation is the early or almost immedi- and clotting factors), stagnation of ow, and clotting
ate reaction of local tissues and their blood vessels to of blood at the site of injury. This aids in limiting the
injury. It typically occurs before the adaptive immune spread of infectious microorganisms. The loss of plasma
response becomes established (see Chapter 15) and is proteins reduces the intracapillary osmotic pressure and
aimed primarily at removing the injurious agent and increases the osmotic pressure of the interstitial uid,
limiting the extent of tissue damage. Acute in amma- increasing uid movement from the vascular compart-
tion can be triggered by a variety of stimuli, including ment into the tissue space and producing the swelling,
infections, immune reactions, blunt and penetrating pain, and impaired function that are the cardinal signs
trauma, physical or chemical agents (e.g., burns, frost- of acute in ammation. The exudation of uid into the
bite, irradiation, caustic chemicals), and tissue necrosis tissue spaces also serves to dilute the offending agent.
from any cause. The increased permeability characteristic of acute
The classic description of in ammation has been in ammation results from formation of endothelial
handed down through the ages. In the rst century AD , gaps in the venules of the microcirculation. Binding of
the Roman physician Aulus Celsus described the local the chemical mediators to endothelial receptors causes
reaction of injury in terms that are now known as the contraction of endothelial cells and separation of inter-
cardinal signs of in ammation. 1 These signs are rubor cellular junctions. This is the most common mechanism
(redness), tum or (swelling), calor (heat), and dolor of vascular leakage and is elicited by histamine, brady-
(pain). In the second century AD , the Greek physician kinin, leukotrienes, and many other classes of chemical
Galen added a fth cardinal sign, functio laesa (loss of mediators.
function). In addition to the cardinal signs that appear Depending on the severity of injury, the vascu-
at the site of injury, systemic manifestations (e.g., fever) lar changes that occur with in ammation follow one
may occur as chemical mediators (e.g., cytokines) pro- of three patterns of responses. 2 The rst pattern is an
duced at the site of in ammation lead to increased im m ediate transient response, which occurs with minor
levels in the plasma. The constellation of systemic injury. It develops rapidly after injury and is usually
manifestations and increases in serum proteins that reversible and of short duration (15 to 30 minutes).
may occur during acute in ammation is known as the The second pattern is an im m ediate sustained response,
acute-phase response. which occurs with more serious types of injury and con-
tinues for several days. It affects all levels of the micro-
circulation (arterioles, capillaries, and venules) and is
S t a g e s o f Ac u t e In a m m a t io n usually due to direct damage of the endothelium by inju-
Acute in ammation has two stages: vascular and cel- rious stimuli, such as burns or the products of bacterial
lular. The vascular stage is characterized by increased infections.2 N eutrophils that adhere to the endothelium
blood ow (vasodilation) and structural changes may also injure endothelial cells. The third pattern is a
(increased vascular permeability) that allow plasma pro- delayed response, in which the increased permeability
teins to leave the circulation. The cellular stage involves begins after a delay of 2 to 12 hours, lasts for several
the emigration of leukocytes (mainly neutrophils) from hours or even days, and involves venules as well as cap-
the microcirculation and their accumulation at the site illaries.2 A delayed response often accompanies injuries
of injury or infection. due to radiation, such as sunburn.

Vas cular S tage Ce llular S tage

The vascular changes that occur with in ammation The cellular stage of acute in ammation is marked by
involve the arterioles, capillaries, and venules of the micro- changes in the endothelial cells lining the vasculature
circulation. These changes begin almost immediately after and movement of phagocytic leukocytes into the area of
(tex t continues on page 56)

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54 U N I T 1 Cell and Tissue Function

U N D E R S TA N D IN G A cu te In fla m m a tio n
Acu te in a m m a tio n is th e im m e d ia te a n d e a rly re s p o n s e to a n in ju rio u s
a g e n t. Th e re s p o n s e , w h ich s e rve s to co n tro l a n d e lim in a te a lte re d ce lls ,
m icro o rga n is m s , a n d a n tig e n s , o ccu rs in tw o p h a s e s : (1) th e va s cu la r
p h a s e , w h ich le a d s to a n in cre a s e in b lo o d o w a n d ch a n g e s in th e s m a ll
b lo o d ve s s e ls o f th e m icro circu la tio n ; a n d (2) th e ce llu la r p h a s e , w h ich le a d s
to th e m ig ra tio n o f le u ko cyte s fro m th e circu la tio n a n d th e ir a ctiva tio n to
e lim in a te th e in ju rio u s a g e n t. Th e p rim a ry fu n ctio n o f th e in a m m a to ry
re s p o n s e is to lim it th e in ju rio u s e ffe ct o f th e p a th o lo g ic a g e n t a n d re m ove
th e in ju re d tis s u e co m p o n e n ts , th e re b y a llo w in g tis s u e re p a ir to ta ke p la ce .

1 Arte riole
Va s c u la r P h a s e . The vascular
phase of acute in ammation is char-
acterized by changes in the small
blood vessels at the site of injury. It
begins with momentary vasocon-
striction followed rapidly by vasodi-
lation. Vasodilation involves the
arterioles and venules with a resul-
tant increase in capillary blood ow
Ve nule
causing heat and redness, which are
two of the cardinal signs of in am-
mation. This is accompanied by an
increase in vascular permeability Va s o c o n s tric tio n
with outpouring of protein-rich uid
(exudate) into the extravascular
spaces. The loss of proteins reduces Arte riole dila tion Exuda te
the capillary osmotic pressure and
increases the interstitial osmotic
pressure. This, coupled with an
increase in capillary pressure, causes
a marked out ow of uid and its
accumulation in the tissue spaces,
producing the swelling, pain, and
impaired function that represent the
other cardinal signs of acute in am-
mation. As uid moves out of the
vessels, stagnation of ow and clot-
ting of blood occur. This aids in
localizing the spread of infectious
Va s o d ila tio n Ve nule dila tion

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C H A P T E R 3 In ammation, the In ammatory Response, and Fever 55

Blood flow
C e llu la r P h a s e : Le u k o c y t e
Endothe lia l ce lls
M a r g in a t io n , Ad h e s io n , a n d
Tr a n s m ig r a t io n . The cellular
phase of acute in ammation
involves the delivery of leukocytes,
mainly neutrophils, to the site of
injury so they can perform their nor- Rolling Firm a dhe s ion Tra ns migra tion
mal functions of host defense. The
delivery and activation of leuko-
cytes can be divided into the follow-
ing steps: adhesion and margination,
transmigration, and chemotaxis. Ca pilla ry
The recruitment of leukocytes to the Ne utrophil
precapillary venules, where they exit
the circulation, is facilitated by the
slowing of blood ow and margin- Ne utrophil
ation along the vessel surface.
2 Tra ns migra tion
Leukocyte adhesion and transmi-
gration from the vascular space into
the extravascular tissue is facilitated 1 Ma rgina tion Ba cte ria
by complementary adhesion mole-
cules (e.g., selectins, integrins) on
the leukocyte and endothelial sur-
faces. After extravasation, leuko-
cytes migrate in the tissues toward
the site of injury by chemotaxis, or 3 Che mota xis
locomotion oriented along a chemi-
cal gradient.

3 1
Le u k o c y t e Ac t iv a t io n and P ha gos ome 2
Fc re ce ptor
P h a g o c y t o s is . O nce at the sight
of injury, the products generated by
tissue injury trigger a number of leu-
kocyte responses, including phago-
cytosis and cell killing. O psonization C3b
of microbes (1) by complement fac- C3b
tor C3b and antibody facilitates rec- re ce ptor
ognition by neutrophil C3b and the
antibody Fc receptor. Receptor acti- 3
vation (2) triggers intracellular sig-
naling and actin assembly in the
neutrophil, leading to formation of
pseudopods that enclose the microbe
within a phagosome. The phago-
some (3) then fuses with an intracel- 4
lular lysosome to form a
phagolysosome into which lyso- P ha golys os ome
somal enzymes and oxygen radicals
(4) are released to kill and degrade
the microbe.

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56 U N I T 1 Cell and Tissue Function

(tex t continued from page 53)

injury or infection. Although attention has been focused containing antibacterial molecules and enzymes that can
on the recruitment of leukocytes from the blood, a rapid kill and digest the microbe (see Chapter 1).
response also requires the release of chemical mediators Intracellular killing of pathogens is accomplished
from certain resident cells in the tissues (mast cells and through several mechanisms, including toxic reactive
macrophages). The sequence of events in the cellular oxygen- and nitrogen-containing species, lysozymes,
response to in ammation includes leukocyte (1) margin- proteases, and defensins. The metabolic burst path-
ation and adhesion, (2) transmigration, (3) chemotaxis, ways that generate toxic reactive oxygen- and nitrogen-
and (4) activation and phagocytosis. 13 containing species (e.g., hydrogen peroxide, nitric
During the early stages of the in ammatory response, oxide) require oxygen and metabolic enzymes such as
signaling between blood leukocytes and the endothelial nicotinamide adenine dinucleotide phosphate (N ADPH )
cells de nes the in ammatory event and ensures arrest oxidase and nitric oxide synthetase. Individuals who are
of the leukocytes along the endothelium.9 As a conse- born with genetic defects in some of these enzymes have
quence, blood owand leukocyte circulationslows. immunode ciency conditions that make them suscep-
This process of leukocyte accumulation is called m ar- tible to repeated bacterial infection.
gination. The subsequent release of cell communication
molecules called cytok ines causes the endothelial cells In am m ato ry Me diato rs
lining the vessels to express cell adhesion molecules that H aving described the events of acute in ammation, we
bind to carbohydrates on the leukocytes. This interac- can now turn to a discussion of the chemical media-
tion, which is called tethering, slows their ow and causes tors responsible for the events. In ammatory mediators
the leukocytes to roll along the endothelial cell surface, may be derived from the plasma or produced locally by
nally coming to rest and adhering strongly to intercellu- cells at the site of in ammation (Fig. 3-3). The plasm a-
lar adhesion molecules on the endothelium.1,2 The adhe- derived m ediators, which are synthesized in the liver,
sion is followed by endothelial cell separation, allowing include the acute-phase proteins, coagulation (clotting)
the leukocytes to extend pseudopodia and transm igrate factors (discussed in Chapter 12), and complement pro-
through the vessel wall and then, under the in uence of teins (discussed in Chapter 15). These mediators are
chemotactic factors, migrate into the tissue spaces. present in the plasma in a precursor form that must be
Chem otax is is a dynamic and energy-directed process activated by a series of proteolytic processes to acquire
of cell migration.1 O nce leukocytes exit the capillary, their biologic properties. Cell-derived m ediators are
they move through the tissue guided by a gradient of normally sequestered in intracellular granules that need
secreted chemoattractants, such as chemokines, bacte- to be secreted (e.g., histamine from mast cells) or newly
rial and cellular debris, and fragments generated from synthesized (e.g., cytokines) in response to a stimulus.
activation of the complement system (see Chapter 15). The major sources of these mediators are platelets, neu-
Chemokines, an important subgroup of chemotactic trophils, monocyte/macrophages, and mast cells, but
cytokines, are small proteins that direct the traf cking most endothelial cells, smooth muscle cells, and bro-
of leukocytes during the early stages of in ammation or blasts can be induced to produce some of the mediators.
injury.13 Several immune (e.g., macrophages) and nonim- M ediators can act on one or a few target cells, have
mune cells secrete these chemoattractants to ensure the diverse targets, or have differing effects on different types
directed movement of leukocytes to the site of infection. of cells. O nce activated and released from the cell, most
During the next and nal stage of the cellular response,
mediators are short-lived. They may be transformed
neutrophils, monocytes, and tissue macrophages are acti- into inactive metabolites, inactivated by enzymes, or
vated to engulf and degrade the bacteria and cellular otherwise scavenged or degraded.
debris in a process called phagocytosis.1,2,14 Phagocytosis
involves three distinct steps: recognition and adherence, Plas m a-De rive d Me diato rs
engulfment, and intracellular killing. It is initiated by rec-
ognition and binding of particles by speci c receptors on The plasma is the source of in ammatory mediators
the surface of phagocytic cells. This binding is essential for that are products of three major protein cascades or
trapping the agent, triggering engulfment, and intracellular systems: the kallikreinkininogen system, which gen-
killing of microbes. M icrobes can be bound directly to the erates kinins; the coagulation system, which includes
membrane of phagocytic cells by several types of pattern the important brin end product; and the complement
recognition receptors (e.g., toll-like and mannose recep- system that includes the various complement proteins.
tors) or indirectly by receptors that recognize microbes Kinins are products of the liver and factors in the coagu-
coated with carbohydrate-binding lectins, antibody, and/ lation system (see Chapter 12). O ne kinin, bradykinin,
or complement (see innate immunity, Chapter 15). The causes increased capillary permeability and pain. The
enhanced binding of an antigen to a coated microbe or coagulation system also contributes to the vascular
particle is called opsonization. Engulfment follows the phase of in ammation mainly through formation of the
recognition of an agent as foreign. During the process of brin mesh formed during the nal steps of the clotting
engulfment, extensions of cytoplasm move around and process. The complement system consists of a cascade of
eventually enclose the particle in a membrane-surrounded plasma proteins that play important roles in both immu-
phagocytic vesicle or phagosome. Once in the cell cyto- nity and in ammation. These proteins contribute to the
plasm, the phagosome fuses with a cytoplasmic lysosome in ammatory response by (1) causing vasodilation and

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C H A P T E R 3 In ammation, the In ammatory Response, and Fever 57

Acute infla mma tion

Live r Ce lls

P la s ma -de rive d me dia tors Ce ll-de rive d me dia tors

Acute -pha s e Fa ctor XII Comple me nt P re forme d Ne wly

prote ins (Ha ge ma n fa ctor) prote ins me dia tors s ynthe s ize d
a ctiva tion

Fe ve r Infla mma tion

Ma s t P la te le ts Ne utrophils Le ukocyte s Le ukocyte s Ma cropha ge s
Activa tion Activa tion Activa tion of ce lls Ma cropha ge s Ma cropha ge s Lymphocyte s
fibrinolytic kinin comple me nt Endothe lia l ce lls
s ys te m s ys te m s ys te m
(bra dykinin)

His ta mine S e rotonin Lys os oma l P ros ta gla ndins Nitric oxide Cytokine s
e nzyme s Le ukotrie ne s Oxyge n-
ROS = re a ctive oxyge n s pe cie s ROS P AF de rive d
P AF = pla te le t-a ctiva ting fa ctor fre e ra dica ls
FIG U RE 3 -3 . Pla s m a - a n d ce ll-d e rive d m e d ia to rs o f a cu te in a m m a tio n .

increasing vascular permeability; (2) promoting leuko- and increases the permeability of venules. It acts at
cyte activation, adhesion, and chemotaxis; and (3) aug- the level of the microcirculation by binding to his-
menting phagocytosis (see Chapter 15). tamine1 (H 1 ) receptors on endothelial cells and is
considered the principal mediator of the immediate
Ce ll-De rive d Me diato rs transient phase of increased vascular permeability in
the acute in ammatory response. Antihistamine drugs
The cell-derived mediators are released from cells that (H 1 receptor antagonists), which bind to the H 1 recep-
are present at sites of in ammation. Tissue macrophages, tors, act to competitively antagonize many of the effects
mast cells, endothelial cells, as well as leukocytes that of the immediate in ammatory response. Serotonin
are recruited to the site from the blood are all capable (5-hydroxytryptamine) is also a preformed vasoactive
of releasing the different mediators of in ammation, as mediator, with effects similar to histamine. It is found
are platelets, which are cellular fragments (see Fig. 3-3). primarily within platelet granules and is released during
platelet aggregation.
His tam ine and S e ro to nin. H istamine and serotonin
are classi ed as vasoactive am ines, meaning they are Arachido nic Acid Me tabo lite s . Arachidonic acid is a
derived from amino acids (histamine from histidine 20-carbon unsaturated fatty acid found in the phospho-
and serotonin from tryptamine) and act by producing lipids of cell membranes. Release of arachidonic acid by
changes in blood vessel tone. Both histamine and sero- phospholipases initiates a series of complex reactions
tonin are stored as preformed molecules in mast cells that lead to the production of the eicosanoid family of
and other cells and are among the rst mediators to be in ammatory mediators (prostaglandins, leukotrienes,
released in acute in ammatory reactions. and related metabolites).15 Eicosanoid synthesis follows
Preformed histamine is widely distributed in tissues, one of two pathways: the cyclooxygenase pathway,
the highest concentrations being found in mast cells which culminates in the synthesis of prostaglandins; and
adjacent to blood vessels.1,2 It is also found in circulat- the lipoxygenase pathway, which culminates in the syn-
ing platelets and basophils and is released in response thesis of the leukotrienes (Fig. 3-4). The corticosteroid
to a variety of stimuli, including trauma and immune drugs block the in ammatory effects of both pathways
reactions involving binding of IgE to basophils and by inhibiting phosphodiesterase activity and thus pre-
mast cells. H istamine produces dilation of arterioles venting the release of arachidonic acid.16

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58 U N I T 1 Cell and Tissue Function

Injure d tis s ue ,
infla mma tory me dia tors

Ce ll me mbra ne phos pholipids

Corticos te roid
me dica tions

Ara chidonic a cid

Lipoxyge na s e Cyclooxyge na s e
pa thwa y pa thwa y

As pirin, NS AIDs

Le ukotrie ne s
(LTC 4 , LTD4 , LTE 4 ) P ros ta gla ndins Thromboxa ne
(P GI2 , P GF 2a ) (TxA2 )

Induce s s mooth mus cle

contra ction Induce s va s odila tion a nd Va s ocons triction
Cons tricts pulmona ry bronchocons triction Bronchocons triction
a irwa ys Inhibits infla mma tory P romote s pla te le t FIG U RE 3 -4 . Th e cyclo oxyg e n a s e a n d
Incre a s e s microva s cula r ce ll function function lip oxyg e n a s e p a th wa ys a n d s ite s w h e re th e
pe rme a bility co rtico s te ro id a n d n o n s te ro id a l a n ti-in a m m a to ry
d ru g s (NSAIDs ) e xe rt th e ir a ctio n .

Several prostaglandins are synthesized from arachi- which is present in ax seed, canola oil, green leafy veg-
donic acid through the cyclooxygenase metabolic path- etables, walnuts, and soybeans, is an essential omega-3
way.15 The prostaglandins (e.g., PGD 2 , PGE2 , PGF2, and fatty acid that cannot be produced in the body and must
PGI2 ) induce in ammation and potentiate the effects of be obtained through the diet. The omega-3 polyun-
histamine and other in ammatory mediators. The pros- saturated fatty acids, which are considered antithrom-
taglandin thromboxane A2 promotes platelet aggrega- botic and anti-in ammatory, are structurally different
tion and vasoconstriction. Aspirin and the nonsteroidal from the prothrombotic and proin ammatory omega-6
anti-in ammatory drugs (N SAIDs) reduce in ammation polyunsaturated fatty acids, which are present in most
by inactivating the rst enzyme in the cyclooxygenase seeds, vegetable oils, and meats. Typically, the cell mem-
pathway for prostaglandin synthesis. branes of in ammatory cells contain high proportions
Like the prostaglandins, the leukotrienes are formed of omega-6 arachidonic acid, which is the source of
from arachidonic acid, but through the lipoxygen- prostaglandin and leukotriene in ammatory mediators.
ase pathway. H istamine and leukotrienes have similar Eating oily sh and other foods that are high in omega-3
functions; however, histamine is produced rapidly and fatty acids results in partial replacement of omega-6
transiently while the more potent leukotrienes are being arachidonic acid in in ammatory cell membranes by
synthesized. The leukotrienes also have been reported eicosapentaenoic acid, a change that leads to decreased
to affect the permeability of the postcapillary venules, production of arachidonic acidderived in ammatory
the adhesion properties of endothelial cells, and the mediators. This response alone is a potentially bene cial
extravasation and chemotaxis of neutrophils, eosino- effect of omega-3 fatty acids. H owever, omega-3 fatty
phils, and monocytes. Leukotriene (LT) C 4 , LTD 4 , and acids may have a number of other anti-in ammatory
LTE4 , collectively known as the slow -reacting substance effects that occur downstream of altered eicosanoid pro-
of anaphylax is (SRS-A), cause slow and sustained con- duction or might be independent of this function.
striction of the bronchioles and are important in am-
matory mediators in bronchial asthma and anaphylaxis. Plate le t-Activating Factor. O riginally named for its
ability to cause platelet aggregation and granulation, PAF
Om e ga-3 Po lyuns aturate d Fatty Acids . There has is another phospholipid-derived mediator with a broad
been recent interest in dietary modi cation of the spectrum of in ammatory effects. Platelet-activating fac-
in ammatory response through the use of om ega-3 tor is generated from the membrane phospholipids of vir-
polyunsaturated fatty acids. These include eicosapentae- tually all activated in ammatory cells and affects a variety
noic acid and docosahex aenoic acid, which are present of cell types. In addition to activating platelets, PAF stim-
in oily sh and sh oil, 17,18 but can be derived in limited ulates neutrophils, monocytes/macrophages, endothelial
quantities from -linolenic acid. The -linolenic acid, cells, and vascular smooth muscle. Platelet activating

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C H A P T E R 3 In ammation, the In ammatory Response, and Fever 59

factor-induced platelet aggregation and degranulation keratinocytes). The secretion of TN F- and IL-1 can
at the site of injury enhances serotonin release, thereby be stimulated by bacterial toxins, immune cells, injury,
causing changes in vascular permeability. It also enhances and a variety of in ammatory stimuli. TN F- and IL-1
leukocyte adhesion, chemotaxis, and leukocyte degranu- induce endothelial cells to express adhesion molecules
lation and stimulates the synthesis of other in ammatory and release other cytokines, chemokines, and reactive
mediators, especially the prostaglandins. oxygen species. Tumor necrosis factor- induces priming
and aggregation of neutrophils, leading to augmented
Cyto kine s and Che m o kine s . Cytokines are low- responses of these cells to other mediators. Interleukin-1
molecular-weight proteins that are important cellular and TN F- are also mediators of the acute-phase
messengers. They modulate the function of cells by responses associated with infection or injury. Features of
paracrine and autocrine mechanisms to cause responses these systemic responses include fever, hypotension and
in neighboring cells and the cells that produced the cyto- increased heart rate, anorexia, release of neutrophils
kine, respectively. They are produced by many cell types, into the circulation, and increased levels of corticoste-
including activated macrophages and lymphocytes, roid hormones.
endothelial cells, epithelial cells, and broblasts.1,2,18 Chemotactic cytokines, or chem ok ines, are a family of
Although well known for their role in adaptive immune small proteins that act primarily as chemoattractants that
responses, these proteins also play important roles in both recruit and direct the migration of in ammatory
both acute and chronic in ammation. and immune cells20 (see Chapter 15). Chemokines gener-
Tumor necrosis factor- (TN F-) and interleukin-1 ate a chemotactic gradient by binding to proteoglycans
(IL-1) are two of the major cytokines that mediate on the surface of endothelial cells or in the extracellu-
in ammation. The major cellular source of TN F- and lar matrix.20 As a result, high concentrations of chemo-
IL-1 is activated macrophages (Fig. 3-5). Interleukin-1 kines persist at sites of tissue injury or infection. Two
is also produced by many other cell types, including classes of chemokines have been identi ed: in amma-
neutrophils, endothelial cells, and epithelial cells (e.g., tory chemokines and homing chemokines. In ammatory
chemokines are produced in response to bacterial toxins
Gra m-ne ga tive and in ammatory cytokines (i.e., IL-1, TN F-). These
ba cte ria T ce lls chemokines recruit leukocytes during an in ammatory
response. H oming chemokines are constantly produced,
with the genes that control their production being
up-regulated during in ammatory reactions.
Ma cropha ge
LP S Nitric Oxide . N itric oxide (N O ), which is produced by
a variety of cells, plays multiple roles in in ammation,
including relaxation of vascular smooth muscle; antag-
onism of platelet adhesion, aggregation, and degranu-
lation; and as regulator of leukocyte recruitment. 2
Blocking of N O production under normal conditions
promotes leukocyte rolling and adhesion to postcapillary
TNF- , IL-1 venules and delivery of exogenous N O reduces leuko-
cyte recruitment. Thus, production of N O appears to be
an endogenous compensatory mechanism that reduces
the cellular phase of in ammation. Impaired production
CELLS RES P ONS E of N O by vascular endothelial cells is implicated in the
in ammatory changes that occur with atherosclerosis
Adhe s ion mole cule s Feve r
Aggre ga tion (see Chapter 18). N itric oxide and its derivatives also
Cytokine s P riming Anorexia have antimicrobial actions, and thus N O is also a host
Eicos a noids Hypote ns ion mediator against infection.
Che mokine s Incre a s e d he a rt ra te
Oxyge n ra dica ls Corticos te roid a nd Re active Oxyge n S pe cie s . Reactive oxygen species
ACTH re le a s e may be released extracellularly from leukocytes after
exposure to microbes, cytokines, and immune com-
plexes, or in the phagocytic process that occurs dur-
FIG U RE 3 -5 . Ce n tra l ro le o f in te rle u kin (IL)-1 a n d tu m o r ing the cellular phase of the in ammatory process. The
n e cro s is fa cto r (TNF)- in in a m m a tio n . Lip o p o lys a cch a rid e superoxide radical, hydrogen peroxide, and hydroxyl
(LPS ) a n d in te rfe ro n (IFN)- a ctiva te m a cro p h a g e s to re le a s e radical (discussed in Chapter 2) are the major species
in a m m a to ry cyto kin e s , p rin cip a lly IL-1 a n d TNF-, re s p o n s ib le
produced within the cell. These species can combine
fo r d ire ctin g b o th lo ca l a n d s ys te m ic in a m m a to ry re s p o n s e s .
ACTH, a d re n o co rtico tro p h ic h o rm o n e . (Fro m Mu rp hy
with N O to form other reactive nitrogen intermedi-
HS . In a m m a tio n . In : Ru b in R, S tra ye r DS , e d s . Ru b ins ates. Extracellular release of low levels of these potent
Pa th o lo g y: Clin ico p a th o lo g ic Fo u n d a tio n s o f Me d icin e . 6th e d . mediators can increase the expression of cytokines and
Ph ila d e lp h ia , PA: Wo lte rs Klu w e r He a lth /Lip p in co tt Willia m s & endothelial adhesion molecules, amplifying the cascade
Wilkin s ; 2012:60.) that elicits the in ammatory process,2 and increase cell

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60 U N I T 1 Cell and Tissue Function

proliferation. H owever, at higher levels these mediators (e.g., foot ulcers associated with diabetes). In chronic
can produce endothelial cell damage, with a resultant lesions where there is repeated insult, the area surrounding
increase in vascular permeability; inactivate antiprote- the ulcer develops broblastic proliferation, scarring,
ases, such as 1 -antitrypsin, which protect against lung and accumulation of chronic in ammatory cells.2
damage in smokers; and produce injury to other cell
types, including red blood cells. 2 Thus, the in uence of
RO S in any in ammatory process depends on a bal- Re s o lu t io n
ance between the generation and inactivation of these
Although the manifestations of acute in ammation are
largely determined by the nature and intensity of injury,
the tissue affected, and the persons ability to mount a
response, the outcome generally results in one of three pro-
Lo c a l M a n if e s t a t io n s cesses: resolution, progression to chronic in ammation,
The local manifestations of acute in ammation, which or substantial scarring and brosis.2 Resolution involves
are determined by severity of the reaction, its speci c the replacement of any irreversibly injured cells and return
cause, and the site of involvement, can range from mild of tissues to their normal structure and function.21,22 It is
swelling and redness to abscess formation or ulceration. seen with short-lived and minimal injuries and involves
As part of the normal defense reaction, in ammation neutralization or degradation of in ammatory mediators,
can also injure adjacent tissues.2 In some infections, normalization of vascular permeability, and cessation of
such as tuberculosis and certain viral infections, the host leukocyte in ltration. Progression to chronic in amma-
response can cause more damage than the microbe itself. tion may follow acute in ammation if the offending agent
As a normal attempt to clear damaged and dead tissues is not removed. Depending on the extent of injury, as well
(e.g., after a myocardial infarction), the in ammatory as the ability of the affected tissues to regenerate, chronic
response may prolong and exacerbate the injurious con- in ammation may be followed by restoration of normal
sequences of the infarction. structure and function. Scarring and brosis occurs when
Characteristically, the acute in ammatory response there is substantial tissue injury or when in ammation
involves the production of exudates. These exudates occurs in tissues that do not regenerate.
vary in terms of uid type, plasma protein content, and Although the mechanisms involved in the resolution
presence or absence of cells. They can be serous, hemor- of acute in ammation have remained somewhat elusive,
rhagic, brinous, membranous, or purulent. O ften the emerging evidence suggests that an active, coordinated
exudate is composed of a combination of these types. program of resolution begins in the rst hours after an
Serous ex udates are watery uids low in protein con- in ammatory response begins.2,21 Studies suggest that
tent that result from plasma entering the in ammatory after entering the site of acute in ammation, neutrophils
site. H em orrhagic ex udates occur when there is severe trigger a switch from the previously described proin am-
tissue injury that causes damage to blood vessels or matory eicosanoids (e.g., prostaglandins and leukotri-
when there is signi cant leakage of red cells from the enes) to other anti-in ammatory classes of eicosanoids,
capillaries. Fibrinous ex udates contain large amounts of also generated from arachidonic acid. These eicosanoids
brinogen and form a thick and sticky meshwork, much initiate the termination sequence during which neutro-
like the bers of a blood clot. M em branous or pseudo- phil recruitment ceases and programmed cell death by
m em branous ex udates develop on mucous membrane apoptosis commences. The apoptotic neutrophils then
surfaces and are composed of necrotic cells enmeshed in undergo phagocytosis by macrophages, leading to their
a bropurulent exudate. clearance and release of anti-in ammatory and repara-
A purulent or suppurative ex udate contains pus, tive cytokines. Although much new information regard-
which is composed of degraded white blood cells, pro- ing the resolution of in ammation has been obtained
teins, and tissue debris. The term pyogenic refers to over the past few years, many issues require further clar-
pus forming. Certain pyogenic microorganisms, such i cation. N ew therapeutic targets are currently being
as Staphylococcus, are more likely to induce localized investigated and potential proresolution properties of
suppurative in ammation than others. An abscess is a existing drugs studied. These discoveries may bring
localized area of in ammation containing a purulent profound advances in therapies aimed at reducing the
exudate. Abscesses typically have a central necrotic core adverse effects of persistent in ammation.
containing purulent exudates surrounded by a layer of
neutrophils.2 Fibroblasts may eventually enter the area
and wall off the abscess. Because antimicrobial agents S UM M A R Y C O N C EP TS
cannot penetrate the abscess wall, surgical incision and
drainage may be required as a cure. Th e cla s s ic s ig n s o f a n a cu te in a m m a to ry
An ulceration refers to a site of in ammation where
re s p o n s e a re re d n e s s , s w e llin g , lo ca l h e a t, p a in ,
an epithelial surface (e.g., skin or gastrointestinal epithe-
a n d lo s s o f fu n ctio n . Th e s e m a n ife s ta tio n s ca n
lium) has become necrotic and eroded, often with asso-
ciated subepithelial in ammation. Ulceration may occur b e a ttrib u te d to th e im m e d ia te va s cu la r ch a n g e s
as the result of traumatic injury to the epithelial surface th a t o ccu r (va s o d ila tio n a n d in cre a s e d ca p illa ry
(e.g., peptic ulcer) or because of vascular compromise

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C H A P T E R 3 In ammation, the In ammatory Response, and Fever 61

cytokines and growth factors that favor tumor develop-

p e rm e a b ility), th e in u x o f in a m m a to ry ce lls ment and growth (see Chapter 7). 23 Among the cancers
s u ch a s n e u tro p h ils , a n d , in s o m e ca s e s , th e associated with chronic infection and in ammation are
w id e s p re a d e ffe cts o f in a m m a to ry m e d ia to rs , cervical cancer (human papillomavirus [H PV]), cancer
w h ich p ro d u ce fe ve r a n d o th e r s ys te m ic s ig n s of the liver (hepatitis B and C), cancer of the stomach
(H elicobacter pylori), and cancer of the gallbladder
a n d s ym p to m s .
(chronic cholecystitis and cholelithiasis).
Ch e m ica l m e d ia to rs a re in te g ra l to in itia tio n ,
a m p li ca tio n , a n d te rm in a tio n o f in a m m a to ry
p ro ce s s e s . Th e p la s m a is th e s o u rce o f m e d ia to rs C a u s e s o f C h ro n ic In a m m a t io n
d e rive d fro m th re e m a jo r p ro te in ca s ca d e s th a t Agents that evoke chronic in ammation typically are
a re a ctiva te d d u rin g in a m m a tio n . Th e s e p ro te in low-grade, persistent infections or irritants that are
ca s ca d e s in clu d e th e ka llikre in -kin in o g e n s ys te m , unable to penetrate deeply or spread rapidly. 1,2 Among
th e co a g u la tio n s ys te m , a n d th e co m p le m e n t the causes of chronic in ammation are foreign agents
s ys te m . Ce ll-d e rive d m e d ia to rs , in clu d in g such as talc, silica, asbestos, and surgical suture mate-
h is ta m in e , b ra d ykin in , th e a ra ch id id o n ic rials. M any viruses provoke chronic in ammatory
m e ta b o lite s , p la te le t a ctiva tin g fa cto r (PAF), a n d responses, as do certain bacteria, such as the tubercle
m a ny o th e rs a re re le a s e d fro m ce lls a t th e s ite o f bacillus and the actinomyces, as well as fungi, and larger
parasites of moderate to low virulence. The presence of
in a m m a tio n .
injured tissue such as that surrounding a healing frac-
Acu te in a m m a tio n m a y invo lve th e p ro d u ctio n ture also may incite chronic in ammation. Diseases
o f e xu d a te s co n ta in in g s e ro u s u id (s e ro u s that cause excessive and inappropriate activation of
e xu d a te ), re d b lo o d ce lls (h e m o rrh a g ic e xu d a te ), the immune system are increasingly being recognized as
b rin o g e n ( b rin o u s e xu d a te ), o r tis s u e d e b ris causes of chronic in ammation. Under certain condi-
a n d w h ite b lo o d ce ll b re a kd o w n p ro d u cts tions, immune reactions may develop against the per-
(p u ru le n t e xu d a te ). sons own tissues, leading to autoimmune disease.
O besity is a newly suspected cause of chronic in am-
Th e o u tco m e o f a cu te in a m m a tio n g e n e ra lly mation.2426 During the last decade, white adipose tis-
re s u lts in o n e o f th re e p ro ce s s e s : re s o lu tio n , sue was recognized to be an active endocrine organ and
p ro g re s s io n to ch ro n ic in a m m a tio n , o r a source of a number of proin ammatory mediators.
s u b s ta n tia l s ca rrin g a n d b ro s is . M any of the mediators appear to play an important role
in the pathogenesis of obesity-related diseases includ-
ing accelerated atherosclerosis and diabetes mellitus.
The link between obesity and in ammation dates back
to the discovery that adipose tissue was a source of the
C h ro n ic In a m m a t io n proin ammatory cytokine TN F-, and that adipose tis-
sue TN F- concentrations are correlated with insulin
In contrast to acute in ammation, which is usually self-
resistance both in persons with and without type 2 dia-
limited and of short duration, chronic in ammation is
betes mellitus. It was later found that obesity is related
self-perpetuating and may last for weeks, months, or
not only to increased number and size of adipocytes,
even years. 1,2,23 It may develop as a result of a recurrent
but also to in ltration of adipose tissue by macrophages
or progressive acute in ammatory process or from low-
that possess the ability to produce TN F-, nitric oxide,
grade, smoldering responses that fail to evoke an acute
and other in ammatory mediators. The mechanisms
response. Instead of the vascular permeability changes,
mediating the proin ammatory state associated with
edema, and predominantly neutrophilic in ltration seen
obesity are still unclear, but recent studies suggest that
in acute in ammation, chronic in ammation is charac-
circulating free fatty acids may play a role.
terized by in ltration with mononuclear cells (macro-
phages, lymphocytes, and plasma cells) and attempted
connective tissue repair involving angiogenesis and
brosis. Although it may follow acute in ammation,
G r a n u lo m a t o u s In a m m a t io n
chronic in ammation often begins insidiously as a low- A granulomatous lesion is a distinctive form of chronic
grade, smoldering, and asymptomatic process. This type in ammation. 1,2 A granuloma typically is a small,
of process is the cause of tissue damage in some of the 1- to 2-mm lesion in which there is a massing of macro-
most common disabling diseases such as atherosclerosis, phages surrounded by lymphocytes. The macrophages
chronic lung disease, rheumatoid arthritis, and in am- are modi ed and, because they resemble epithelial cells,
matory bowel disease. sometimes are called epithelioid cells. Like other mac-
There is also evidence that recurrent and persistent rophages, these epithelioid cells are derived originally
in ammation induces, promotes, and/or in uences sus- from blood monocytes. Granulomatous in ammation is
ceptibility to cancer by causing deoxyribonucleic acid associated with foreign bodies such as splinters, sutures,
(DN A) damage, inciting tissue reparative proliferation, silica, and asbestos and with microorganisms that
and/or creating an environment that is enriched with cause tuberculosis, syphilis, sarcoidosis, deep fungal

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62 U N I T 1 Cell and Tissue Function

S y s t e m ic M a n if e s t a t io n s o f
In a m m a t io n
Under optimal conditions, the in ammatory response
remains con ned to a localized area. In some cases,
however, local injury can result in prominent systemic
manifestations as in ammatory mediators are released
into the circulation. The most prominent systemic
manifestations of in ammation include the acute-phase
response, alterations in white blood cell count (leuko-
cytosis or leukopenia), and fever. Localized acute and
chronic in ammation may extend to the lymphatic
system and lead to a reaction in the lymph nodes that
drain the affected area. Painful palpable lymph nodes
FIG U RE 3 -6 . Fo re ig n b o d y g ia n t ce ll. Th e n u m e ro u s n u cle i a re
are more commonly associated with in ammatory pro-
ra n d o m ly a rra n g e d in th e cyto p la s m . (Fro m Ru b in E, Fa rb e r LL.
Ru b ins Pa th o lo g y: Clin ico p a th o lo g ic Fo u n d a tio n s o f Me d icin e .
cesses, whereas nonpainful nodes are more characteris-
3rd e d . Ph ila d e lp h ia , PA: Lip p in co tt Willia m s & Wilkin s ; tic of neoplasms.

Ac u t e -P h a s e Re s p o n s e
infections, and brucellosis. These types of agents have
one thing in common: they are poorly degraded and Along with the cellular responses that occur during
usually are not easily controlled by other in ammatory the in ammatory response, a constellation of systemic
mechanisms. The epithelioid cells in granulomatous effects called the acute-phase response occurs. 1,2 The
in ammation may clump in a mass or coalesce, forming acute-phase response, which usually begins within
a multinucleated giant cell (often referred to as a foreign hours or days of the onset of in ammation or infec-
body giant cell) that attempts to surround the foreign tion, includes changes in the concentrations of plasma
agent (Fig. 3-6). A dense membrane of connective tissue proteins, skeletal muscle catabolism, negative nitro-
eventually encapsulates the lesion and isolates it. gen balance, elevated erythrocyte sedimentation rate,
and increased numbers of leukocytes. O ther mani-
festations of the acute-phase response include fever,
increased heart rate, anorexia, somnolence, and
S U M M A R Y C O N C EP TS malaise.

Acute -Phas e Pro te ins

Ch ro n ic in a m m a tio n invo lve s in ltra tio n w ith
m a cro p h a g e s , lym p h o cyte s , a n d b ro b la s ts , During the acute-phase response, the liver dramatically
le a d in g to p e rs is te n t in a m m a tio n , b ro b la s t increases the synthesis of acute-phase proteins such as
p ro life ra tio n , a n d s ca r fo rm a tio n .
brinogen, C-reactive protein (CRP), and serum amy-
loid A protein (SAA) that serve several different defense
Am o n g th e co n d itio n s a s s o cia te d w ith ch ro n ic functions.1,2 The synthesis of these proteins is stimulated
in a m m a tio n a n d in a p p ro p ria te a ctiva tio n o f by cytokines, especially TN F-, IL-1 (for SAA), and IL-6
th e im m u n e s ys te m a re lo w-g ra d e in a m m a tio n (for brinogen and CRP).
a sso ciated with a th erosclerosis an d typ e 2 diab etes C-reactive protein was named because it precipitated
m e llitu s ; a u to im m u n e d is o rd e rs ; a n d s u s ce p tib ility with the C fraction (C polypeptide) of pneumococci. The
to ca n ce r d u e to d e oxyrib o n u cle ic a cid d a m a g e , function of CRP is thought to be protective, in that it binds
in cre a s e d tis s u e p ro life ra tio n , a n d cre a tio n o f a n
to the surface of invading microorganisms and targets them
for destruction by complement and phagocytosis. Although
e nviron m en t rich in cyto kines an d growth facto rs
everyone maintains a low level of CRP, this level rises when
th a t fa vo r tu m o r ce ll d e ve lo p m e n t a n d g ro w th . there is an acute in ammatory response.27 Recent interest
A g ra n u lo m a to u s le s io n is a d is tin ctive fo rm has focused on the use of high-sensitivity CRP (hsCRP)
o f ch ro n ic in a m m a tio n ch a ra cte rize d b y serum measurements as a marker for increased risk of
a g g re ga te s o f e p ith e lio id m a cro p h a g e s th a t myocardial infarction in persons with coronary heart dis-
wa ll o ff th e ca u s a l a g e n t. Gra n u lo m a to u s ease.28,29 It is believed that in ammation involving athero-
in a m m a tio n is a s s o cia te d w ith fo re ig n b o d ie s
sclerotic plaques in coronary arteries may predispose to
thrombosis and myocardial infarction (see Chapter 18).
s u ch a s s p lin te rs , s u tu re s , s ilica , a n d a s b e s to s
During the acute-phase response, SAA protein
a n d w ith m icro o rga n is m s th a t ca u s e tu b e rcu lo s is , replaces apolipoprotein A, a component of high-density
s yp h ilis , s a rco id o s is , d e e p fu n ga l in fe ctio n s , a n d lipoprotein (H DL) particles (see Chapter 18). This pre-
b ru ce llo s is . sumably increases the transfer of H DLs from liver cells
to macrophages, which can then utilize these particles

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C H A P T E R 3 In ammation, the In ammatory Response, and Fever 63

for energy. The rise in brinogen causes red blood cells

to form stacks (rouleaux) that settle or sediment more 38
rapidly than individual erythrocytes. This is the basis

for the accelerated erythrocyte sedimentation rate (ESR)

that occurs in disease conditions characterized by the 37

systemic in ammatory response.


White Blo o d Ce ll Re s po ns e

Leukocytosis, or the increase in white blood cells, is a fre-

quent sign of an in ammatory response, especially those 6 AM Noon 6 PM Midnight 6 AM
caused by bacterial infection. In acute in ammatory condi-
tions, the white blood cell count commonly increases from
a normal value of 4000 to 10,000 cells/L to 15,000 to FIG U RE 3 -7. No rm a l d iu rn a l va ria tio n s in b o d y te m p e ra tu re .
20,000 cells/L. After being released from the bone mar-
row, circulating neutrophils have a life span of only about changes in temperature. M etabolic processes speed up
10 hours and therefore must be constantly replaced if their or slow down depending on whether body temperature
numbers are to be adequate. With excessive demand for is rising or falling.
phagocytes, immature forms of neutrophils (bands) are Body temperature, which re ects the difference
released from the bone marrow. The phrase a shift to the between heat production and heat loss, is regulated by
left in a white blood cell differential count refers to the the therm oregulatory center in the hypothalamus. Body
increase in immature neutrophils seen in severe infections. heat is generated in the tissues of the body, transferred to
Bacterial infections produce a relatively selective the skin surface by the blood, and then released into the
increase in neutrophils (neutrophilia), while parasitic environment surrounding the body. The thermoregula-
and allergic responses induce eosinophilia. Viral infec- tory center regulates the temperature of the deep body
tions tend to produce a decrease in neutrophils (neutro- tissues, or core of the body, rather than the surface
penia) and an increase in lymphocytes (lymphocytosis).3 temperature. It does so by integrating input from cold
A decrease in white blood cells (leukopenia) may also and warmth receptors located throughout the body and
occur in persons with overwhelming infections or participating in negative feedback mechanisms.
impaired ability to produce white blood cells. The therm ostatic set point of the thermoregulatory
center is the level at which body temperature is regu-
Sys te m ic In am m ato ry Re s po ns e
lated so that core temperature is maintained within
In severe bacterial infections (sepsis), the large quantities the normal range. When body temperature begins to
of microorganisms in the blood result in an uncontrolled rise above this set point, heat-dissipating behaviors are
in ammatory response with the production and release initiated, and when the temperature falls below the set
of enormous quantities of in ammatory cytokines (most point, heat production is increased. A core temperature
notably IL-1 and TN F-) and development of what is greater than 41C (105.8F) or less than 34C (93.2F)
referred to as the system ic in am m atory response syn- usually indicates that the bodys thermoregulatory abil-
drom e (see Chapter 20). 30 A decrease in total white ity is impaired (Fig. 3-8). Body responses that produce,
blood cells (leukopenia) may occur in persons with conserve, and dissipate heat are described in Table 3-1.
overwhelming infections or impaired ability to produce Spinal cord injuries that transect the cord at T6 or above
white blood cells. can seriously impair temperature regulation because the
hypothalamus no longer can control skin blood ow or
Fe ve r In addition to physiologic thermoregulatory mecha-
nisms, humans engage in voluntary behaviors to help
Fever (pyrexia) is an elevation in body temperature
regulate body temperature. These behaviors include the
caused by an upward displacement of the set point of
selection of proper clothing and regulation of environ-
the thermoregulatory center in the hypothalamus. 3133
mental temperature through heating systems and air
It is one of the most prominent manifestations of the
conditioning. Body positions that hold the extremities
acute-phase response.1,2
close to the body (e.g., huddling) prevent heat loss and
Bo dy Te m pe rature Re g ulatio n are commonly assumed in cold weather.

The temperature in the deep tissues of the body (core Me chanis m s o f He at Pro ductio n. M etabolism is the
temperature) is normally maintained within a range bodys main source of heat production. The sympathetic
of 36.0C to 37.5C (97.0F to 99.5F). 31,32 Within neurotransmitters epinephrine and norepinephrine,
this range, there are individual differences and diurnal which are released when an increase in body temperature
variations; internal core temperatures reach their high- is needed, act at the cellular level to shift body metabo-
est point in late afternoon and evening and their lowest lism to heat production rather than energy generation.
point in the early morning hours (Fig. 3-7). Virtually This may be one of the reasons fever tends to produce
all biochemical processes in the body are affected by feelings of weakness and fatigue. Thyroid hormone

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64 U N I T 1 Cell and Tissue Function

muscle tone, followed by an oscillating rhythmic tremor

F C involving the spinal-level re ex that controls muscle
114 Uppe r limits
of s urviva l Te mpe ra ture tone. Because no external work is performed, all of the
He a ts troke re gula tion energy liberated by the metabolic processes from shiver-
Bra in le s ions s e rious ly ing is in the form of heat. Contraction of the pilom otor
42 impa ire d m uscles of the skin, which raises the skin hair and pro-
duces goose bumps, reduces the surface area available
40 Fe brile dis e a s e Te mpe ra ture
a nd
for heat loss.
102 re gula tion
ha rd e xe rcis e e fficie nt in
Physical exertion also increases body temperature.
Us ua l ra nge fe brile dis e a s e , With strenuous exercise, more than three fourths of
98 the increased metabolism resulting from muscle activ-
of norma l he a lth, a nd work
ity appears as heat within the body, and the remainder
appears as external work.

90 32 Te mpe ra ture Me chanis m s o f He at Lo s s . M ost of the bodys heat is

re gula tion produced by the deeper core tissues (i.e., muscles and
impa ire d viscera) and then transferred in the blood to the body
86 30
surface, where it is released into the environment.
There are numerous arteriovenous (AV ) shunts under
82 the skin surface that allow blood to move directly from
Te mpe ra ture the arterial to the venous system. 31 These AV shunts
26 re gula tion
78 are much like the radiators in a heating system. When
los t
the shunts are open, body heat is freely dissipated to the
74 skin and surrounding environment; when the shunts are
closed, heat is retained in the body. The blood ow in
FIG U RE 3 -8 . Bo d y te m p e ra tu re s u n d e r d iffe re n t co n d itio n s .
the AV shunts is controlled almost exclusively by the
(Fro m Du b o is EF. Fe ve r a n d th e Re g u la tio n o f Bo d y
Te m p e ra tu re . S p rin g e ld , IL: Ch a rle s C. Th o m a s ; 1948.) sympathetic nervous system in response to changes in
core temperature and environmental temperature. The
transfer of heat to the bodys surface is in uenced by
increases cellular metabolism, but this response usually blood volume. In hot weather, the body compensates
requires several weeks to reach maximal effectiveness. by increasing blood volume as a means of dissipating
Fine involuntary actions such as shivering and chat- heat. Exposure to cold produces a cold diuresis and a
tering of the teeth can produce a threefold to vefold reduction in blood volume as a means of controlling the
increase in body temperature. Shivering is initiated transfer of heat to the bodys surface.
by impulses from the hypothalamus. The rst muscle H eat is lost from the body through radiation and
change that occurs with shivering is a general increase in conduction from the skin surface; through evaporation

TA BLE 3 - 1 He at Gain and He at Lo s s Re s po ns e s Us e d in Re g ulatio n o f Bo dy Te m pe rature

He a t G a in He a t Lo s s

Bo d y Re s p o n s e M e c h a n is m o f Ac t io n Bo d y Re s p o n s e M e c h a n is m o f Ac t io n

Va s o co n s trictio n o f th e Co n n e s b lo o d o w to th e Dila ta tio n o f De live rs b lo o d co n ta in in g

s u p e r cia l b lo o d ve s s e ls in n e r co re o f th e b o d y, w ith th e s u p e r cia l co re h e a t to th e p e rip h e ry
th e s kin a n d s u b cu ta n e o u s b lo o d ve s s e ls w h e re it is d is s ip a te d
tis s u e s a ctin g a s in s u la tio n th ro u g h ra d ia tio n ,
to p re ve n t lo s s o f co re h e a t co n d u ctio n , a n d co nve ctio n
Co n tra ctio n o f th e p ilo m o to r Re d u ce s h e a t lo s s fro m th e s kin S w e a tin g In cre a s e s h e a t lo s s th ro u g h
m u s cle s th a t s u rro u n d th e e va p o ra tio n
h a irs o n th e s kin
As s u m p tio n o f th e h u d d le Re d u ce s th e s u rfa ce a re a fo r h e a t
p o s itio n w ith th e e xtre m itie s lo s s
h e ld clo s e to th e b o d y
S h ive rin g In cre a s e s h e a t p ro d u ctio n b y
th e m u s cle s
In cre a s e d p ro d u ctio n o f In cre a s e s th e h e a t p ro d u ctio n
e p in e p h rin e a s s o cia te d w ith m e ta b o lis m
In cre a s e d p ro d u ctio n o f Is a lo n g -te rm m e ch a n is m th a t
thyro id h o rm o n e in cre a s e s m e ta b o lis m a n d
h e a t p ro d u ctio n

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C H A P T E R 3 In ammation, the In ammatory Response, and Fever 65

of sweat and insensible perspiration; through exhala- such as convulsions, hypermetabolic states, or direct
tion of air that has been warmed and humidi ed; and impairment of the temperature control center.
through heat lost in urine and feces. O f these mecha-
nisms, only heat losses that occur at the skin surface are Caus e s o f Fe ve r. Fever can be caused by a number
directly under hypothalamic control. of microorganisms and substances that are collec-
R adiation involves the transfer of heat through the tively called pyrogens. 3335 M any proteins, including
air or a vacuum. H eat loss through radiation varies with lipopolysaccharide toxins released from bacterial cell
the temperature of the environment. Environmental tem- membranes, can raise the set point of the hypothalamic
perature must be less than that of the body for heat loss thermostat. N oninfectious disorders, such as myocar-
to occur. About 60% of body heat loss typically occurs dial infarction and pulmonary emboli, also produce
through radiation.31 Conduction involves the direct fever. In these conditions, the injured or abnormal cells
transfer of heat from one molecule to another. Blood incite the production of fever-producing pyrogens. Some
carries, or conducts, heat from the inner core of the malignant cells, such as those of leukemia and H odgkin
body to the skin surface. N ormally, only a small amount disease, also secrete pyrogens.
of body heat is lost through conduction to a cooler sur- Some pyrogens act directly and immediately on the
face. Cooling blankets and mattresses that are used for hypothalamic thermoregulatory center to increase its set
reducing fever rely on conduction of heat from skin to point. O ther pyrogens, often referred to as ex ogenous
the cooler surface of the mattress or blanket. H eat can pyrogens, act indirectly and may require several hours to
also be conducted in the opposite directionfrom the produce their effect.31 Exogenous pyrogens induce host
external environment to the body surface. For instance, cells, such as blood leukocytes and tissue macrophages,
body temperature may rise slightly after a hot bath. to produce fever-producing mediators called endoge-
Convection refers to heat transfer through the cir- nous pyrogens (e.g., IL-1). For example, the breakdown
culation of air currents. N ormally, a layer of warm air products of phagocytosed bacteria that are present in
tends to remain near the bodys surface; convection the blood lead to the release of endogenous pyrogens.
causes continual removal of the warm layer and replace- The endogenous pyrogens are thought to increase the
ment with air from the surrounding environment. The set point of the hypothalamic thermoregulatory center
wind-chill factor that often is included in the weather through the action of prostaglandin E2 (PGE2 ) (Fig. 3-9).31
report combines the effect of convection caused by wind In response to the sudden increase in set point, the hypo-
with the still-air temperature. thalamus initiates heat production behaviors (shivering
Evaporation involves the use of body heat to con- and vasoconstriction) that increase the core body tem-
vert water on the skin to water vapor. Water that dif- perature to the new set point, and fever is established.
fuses through the skin independent of sweating is called A fever that has its origin in the central nervous sys-
insensible perspiration. Insensible perspiration losses are tem is sometimes referred to as a neurogenic fever.36
greatest in a dry environment. Sweating occurs through It usually is the result of damage to the hypothalamus
the sweat glands and is controlled by the sympathetic caused by central nervous system trauma, intracere-
nervous system, using acetylcholine as a neurotrans- bral bleeding, or an increase in intracranial pressure.
mitter. This means that anticholinergic drugs, such as N eurogenic fevers are characterized by a high tempera-
atropine, can interfere with heat loss by interrupting ture that is resistant to antipyretic therapy and is not
sweating. associated with sweating.
Evaporative heat losses involve both insensible per-
spiration and sweating, with 0.58 calorie being lost for Purpo s e o f Fe ve r. The purpose of fever is not com-
each gram of water that is evaporated.31 As long as body pletely understood. H owever, from a purely practical
temperature is greater than the atmospheric tempera- standpoint, fever signals the presence of an infection
ture, heat is lost through radiation. H owever, when the and may legitimize the need for medical treatment. In
temperature of the surrounding environment becomes ancient times, fever was thought to cook the poisons
greater than skin temperature, evaporation is the only that caused the illness. With the availability of anti-
way the body can rid itself of heat. Any condition that pyretic drugs in the late 19th century, the belief that
prevents evaporative heat losses causes the body tem- fever was useful began to wane, probably because most
perature to rise. antipyretic drugs also had analgesic effects.

Fe ve r Patte rns . The patterns of temperature change in

The Fe brile Re s po ns e
persons with fever vary and may provide information
Fever, or pyrexia, describes an elevation in body tem- about the nature of the causative agent.37 These pat-
perature that is caused by a cytokine-induced upward terns can be described as intermittent, remittent, sus-
displacement of the set point of the hypothalamic ther- tained, or relapsing (Fig. 3-10). An intermittent fever
moregulatory center. It is resolved when the factor that is one in which temperature returns to normal at least
caused the increase in the set point is removed. Fevers once every 24 hours. Intermittent fevers are commonly
that are regulated by the hypothalamus usually do not associated with conditions such as gram-negative/-pos-
rise above 41C (105F), suggesting a built-in thermo- itive sepsis, abscesses, and acute bacterial endocarditis.
static regulatory mechanism. Temperatures above that In a remittent fever, the temperature does not return
level are usually the result of superimposed activity, to normal and varies a few degrees in either direction.

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66 U N I T 1 Cell and Tissue Function

Hypotha la mus :
The rmos ta tic
s e t point

4. Core body te mpe ra ture

re a che s ne w s e t point

FIG U RE 3 -9 . Me ch a n is m s o f fe ve r.
2. Re s e tting
(1) Relea se of pro s tag lan d in E2 (PGE2)
the rmos ta tic 5. Te mpe ra ture -re ducing
re s pons e s : o r fe ver-p ro d u cin g cyto kin es fro m
s e t point
Va s odila tion in a m m ato ry ce lls, (2) res etting of
3. Te mpe ra ture -ra is ing S we a ting the therm oregulatory set point in the
1. Re le a s e of P GE 2 re s pons e s : Incre a s e d ve ntila tion hyp oth alam u s to a h ighe r le vel (pro drom e),
or fe ve r-producing Va s ocons triction (3) gen era tion of hyp o tha lam ic-m ed iated
cytokine s from S hive ring res po n ses th at raise b o d y tem p e rature (chill),
infla mma tory ce lls P iloe re ction (4) develop m en t of fe ver w ith elevation of
Incre a s e d me ta bolis m b o d y to n ew th erm o sta tic set p o in t, and
(5) pro d u ction of tem pe rature -lowe ring
res p onses ( us h a nd d e fervescence) a nd
Fe ve r retu rn o f b ody tem peratu re to a lo wer le vel.

In a sustained or continuous fever, the temperature Critical to the analysis of a fever pattern is the rela-
remains above normal with minimal variations (usually tion of heart rate to the level of temperature elevation.
less than 0.55C or 1F). Sustained fevers are seen in per- M ost persons respond to an increase in temperature
sons with drug-induced fever in which a drug inadver- with an appropriate increase in heart rate. The observa-
tently leads to a hypermetabolic fever-inducing state. 38 A tion that a rise in temperature is not accompanied by
recurrent or relapsing fever is one in which there is one the anticipated change in heart rate can provide useful
or more episodes of fever, each as long as several days, information about the cause of the fever. For example, a
with one or more days of normal temperature between heart rate that is slower than would be anticipated can
episodes. Relapsing fevers may be caused by a variety of occur with Legionnaires disease and drug fever, and a
infectious diseases, including tuberculosis, fungal infec- heart rate that is more rapid than anticipated can be
tions, Lyme disease, and malaria. symptomatic of hyperthyroidism.

Inte rmitte nt fe ve r S us ta ine d fe ve r

40.6 40.6
40.0 40.0
39.4 39.4
38.9 38.9
38.3 38.3
37.8 37.8
37.2 37.2
36.7 36.7
A 1 2 3 4 5 C 1 2 3 4 5
Da ys Da ys

Re mitte nt fe ve r Re la ps ing fe ve r
40.6 40.6
40.0 40.0
39.4 39.4
38.9 38.9
38.3 38.3
37.8 37.8
37.2 37.2
36.7 36.7
B 1 2 3 4 5 1 2 3 4 5
Da ys Da ys
FIG U RE 3 -1 0 . Sch e m a tic re p re s e n ta tio n o f fe ve r p a tte rn s : (A) in te rm itte n t, (B) re m itte n t, (C) s u s ta in e d ,
a n d (D) re cu rre n t o r re la p s in g .

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C H A P T E R 3 In ammation, the In ammatory Response, and Fever 67

Manife s tatio ns o f Fe ve r H erpetic lesions, or fever blisters, develop in some

persons during fever. They are caused by a separate
The physiologic behaviors that occur during the develop- infection by the type 1 herpes simplex virus that estab-
ment of fever can be divided into four successive stages: lished latency in the regional ganglia and is reactivated
a prodrome; a chill, during which the temperature rises; by a rise in body temperature.
a ush; and defervescence (see Fig. 3-9). During the rst
or prodrom al period, there are nonspeci c complaints, Manage m e nt o f Fe ve r
such as mild headache and fatigue, general malaise,
and eeting aches and pains. During the second stage Fever usually is a manifestation of a disease state, and
or chill, there is the uncomfortable sensation of being as such, determining the cause of a fever is an impor-
cold and the onset of generalized shaking, although the tant aspect of its treatment. Sometimes it is dif cult to
temperature is rising. Vasoconstriction and piloerection establish the cause. A prolonged fever for which the
usually precede the onset of shivering. At this point the cause is dif cult to ascertain is often referred to as fever
skin is pale and covered with goose esh. There is an of unk now n origin (FUO ). Fever of unknown origin is
urge to put on more clothing or covering and to curl up de ned as a temperature of 38.3C (101F) or higher that
in a position that conserves body heat. When the shiver- is present for 3 weeks or longer.40,41 Among the causes
ing has caused the body temperature to reach the new of FUO are malignancies (i.e., lymphomas, metastases
set point of the temperature control center, the shiver- to the liver or central nervous system); infections such
ing ceases, and a sensation of warmth develops. At this as human immunode ciency virus or tuberculosis, or
point, the third stage or ush begins, during which cuta- abscessed infections; and drug fever. M alignancies, par-
neous vasodilatation occurs and the skin becomes warm ticularly non-H odgkin lymphoma, are important causes
and reddened. The fourth, or defervescence, stage of the of FUO in the elderly. Cirrhosis of the liver is another
febrile response is marked by the initiation of sweat- cause of FUO .
ing. N ot all persons proceed through all four stages of The methods of fever treatment focus on modi ca-
fever development. Sweating may be absent, and fever tions of the external environment intended to increase
may develop gradually, with no indication of a chill or heat transfer from the internal to the external environ-
shivering. ment, support of the hypermetabolic state that accom-
Common manifestations of fever are anorexia, myal- panies fever, protection of vulnerable body organs and
gia, arthralgia, and fatigue. These discomforts are worse systems, and treatment of the infection or condition
when the temperature rises rapidly or exceeds 39.5C causing the fever. Because fever is a disease symptom,
(103.1F). Respiration is increased, and the heart rate its manifestation suggests the need for treatment of the
usually is elevated. Dehydration occurs because of primary cause.
sweating and the increased vapor losses caused by the M odi cation of the environment ensures that the
rapid respiratory rate. The occurrence of chills com- environmental temperature facilitates heat transfer
monly coincides with the introduction of pyrogen into away from the body. Sponge baths with cool water or
the circulation. This is one of the reasons that blood an alcohol solution can be used to increase evaporative
cultures to identify the organism causing the fever are heat losses. M ore profound cooling can be accomplished
usually drawn during the rst signs of a chill. through the use of a cooling blanket or mattress, which
M any of the manifestations of fever are related to facilitates the conduction of heat from the body into the
the increases in the metabolic rate, increased need for coolant solution that circulates through the mattress.
oxygen, and use of body proteins as an energy source. Care must be taken so that cooling methods do not pro-
During fever, the body switches from using glucose (an duce vasoconstriction and shivering that decrease heat
excellent medium for bacterial growth) to metabolism loss and increase heat production.
based on protein and fat breakdown. With prolonged Adequate uids and suf cient amounts of simple
fever, there is increased breakdown of endogenous fat carbohydrates are needed to support the hypermeta-
stores. If fat breakdown is rapid, metabolic acidosis may bolic state and prevent the tissue breakdown that is
result (see Chapter 8). characteristic of fever. Additional uids are needed for
H eadache is a common accompaniment of fever and sweating and to balance the insensible water losses
is thought to result from the vasodilatation of cerebral from the lungs that accompany an increase in respira-
vessels occurring with fever. Delirium is possible when tory rate. Fluids also are needed to maintain an ade-
the temperature exceeds 40C (104F). In the elderly, quate vascular volume for heat transport to the skin
confusion and delirium may follow moderate elevations surface.
in temperature. Because of the increasingly poor oxy- Antipyretic drugs, such as aspirin, ibuprofen, and
gen uptake by the aging lung, pulmonary function may acetaminophen, often are used to alleviate the discom-
prove to be a limiting factor in the hypermetabolism forts of fever and protect vulnerable organs, such as the
that accompanies fever in older persons. Confusion, brain, from extreme elevations in body temperature.
incoordination, and agitation commonly re ect cere- These drugs act by resetting the hypothalamic tem-
bral hypoxemia. Febrile seizures can occur in some perature control center to a lower level, presumably by
children.39 They usually occur with rapidly rising tem- blocking the activity of cyclooxygenase, an enzyme that
peratures and/or at a threshold temperature that differs is required for the conversion of arachidonic acid to
with each child. prostaglandin E2 .

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68 U N I T 1 Cell and Tissue Function

parents or caregivers are deemed reliable. O lder chil-

dren with fever without source also may be treated on
Fe ve r in Childre n
an outpatient basis.
Fever occurs frequently in infants and young children
(i.e., ages 1 day to 3 years) and is a common reason for
visits to the clinic or emergency department.42,43 The dif- Fe ve r in the Elde rly
ferential diagnosis of fever is broad and includes both
infectious and noninfectious causes, with the majority In the elderly, even slight elevations in temperature may
of febrile children having an underlying infection. The indicate serious infection, most often caused by bacteria,
most common causes are minor or more serious infec- or disease. This is because the elderly often have a lower
tions of the respiratory system, gastrointestinal tract, baseline temperature (36.4C [97.6F] in one study)
urinary tract, or central nervous system. The epidemiol- than younger persons, and although their temperature
ogy of serious bacterial disease has changed dramatically increases during an infection, it may fail to reach a level
with the introduction of the H aem ophilus in uenzae that is equated with signi cant fever. 45,46 Therefore, it
and Streptococcus pneum oniae vaccines in developed has been recommended that the de nition of fever in the
countries. H . in uenzae type b has been nearly elimi- elderly be expanded to include an elevation of tempera-
nated and the incidence of pneumococcal disease has ture of at least 1.1C (2F) above baseline values.
declined substantially. Febrile children who are younger The absence of fever may delay diagnosis and initia-
than 1 year of age and females between 1 and 2 years of tion of antimicrobial treatment. Unexplained changes in
age should be considered at risk for a urinary tract infec- functional capacity, worsening of mental status, weak-
tion (see Chapter 24). ness and fatigue, and weight loss are signs of infection
While most children have identi able causes for their in the elderly and should be viewed as possible signs of
fevers, many have fevers without localizing signs or infection and sepsis when fever is absent. A thorough
symptoms. These fevers, which are usually of rapid onset history and physical examination are critically impor-
and present for less than a week, are commonly referred tant.47 The probable mechanisms for the blunted fever
to as fever w ithout source. The American College of response include a disturbance in sensing of tempera-
Emergency Physicians has developed clinical guidelines ture by the thermoregulatory center in the hypothala-
for use in the treatment of previously healthy infants mus, alterations in release of endogenous pyrogens, and
and children ages 1 day to 3 years with fever without a the failure to elicit responses such as vasoconstriction
source. The guidelines de ne fever in this age group as a of skin vessels, increased heat production, and shiver-
rectal temperature of at least 38C (100.4F). The reli- ing that increase body temperature during a febrile
ability of other methods of temperature measurements response.
(e.g., axillary, ear) is lower and must be considered when Another factor that may delay recognition of fever in
making decisions about the seriousness of the fever.43 the elderly is the method of temperature measurement.
The approach to the young child who has fever with- Oral temperature remains the most commonly used
out a source varies depending on the age of the child method, but research suggests that rectal and tympanic
(neonate [0 to 28 days], young infant [1 to 3 months], membrane methods are more effective in detecting fever
and older infants and toddlers [3 to 36 months]).44 All in the elderly.47 This is because conditions such as mouth
have decreased immunologic function and are more com- breathing, tongue tremors, and agitation often make it dif-
monly infected with virulent organisms. N eonates are at cult to obtain accurate oral temperatures in the elderly.
particularly high risk for serious bacterial infections that
can cause bacteremia or meningitis. Also, neonates and
young infants demonstrate limited signs of infection,
often making it dif cult to distinguish between seri- S UM M A R Y C O N C EP TS
ous bacterial infections that require immediate medical
attention and other causes of an elevated temperature.
Fever without source in children younger than age Th e s ys te m ic m a n ife s ta tio n s o f in a m m a tio n
3 months requires careful history and physical exami- in clu d e th e e ffe cts o f th e a cu te -p h a s e re s p o n s e ,
nation.42 The temperature-lowering response to anti- s u ch a s fe ve r a n d le th a rg y; in cre a s e d e ryth ro cyte
pyretic medications does not change the likelihood of a s e d im e n ta tio n ra te (ES R), le ve ls o f C-re a ctive
child having a serious bacterial infection and should not p ro te in (CRP), o th e r a cu te -p h a s e p ro te in s , a n d
be used as an indicator of infection severity.45 N eonates w h ite b lo o d ce lls ; a n d e n la rg e m e n t o f th e lym p h
with signs of toxicity (and high risk) including leth- n o d e s th a t d ra in th e a ffe cte d a re a . In s e ve re
argy, poor feeding, hypoventilation, poor tissue oxy- b a cte ria l in fe ctio n s (s e p s is ), la rg e q u a n titie s
genation, and cyanosis usually require hospitalization o f m icro o rga n is m s in th e b lo o d re s u lt in th e
and treatment with antibiotics. Diagnostic tests such as
p ro d u ctio n a n d re le a s e o f e n o rm o u s q u a n titie s
white blood cell count, blood and urine cultures, chest
o f in a m m a to ry cyto kin e s a n d d e ve lo p m e n t o f
radiographs, and lumbar puncture usually are done to
determine the cause of fever. Infants with fever who w h a t is re fe rre d to a s th e s ys te m ic in a m m a to ry
are considered to be at low risk for bacterial infections re s p o n s e s yn d ro m e .
often are managed on an outpatient basis provided the

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C H A P T E R 3 In ammation, the In ammatory Response, and Fever 69

4. A 3-year-old child is seen in a pediatric clinic with

Fe ve r, a n e le va tio n in b o d y te m p e ra tu re , is o n e a temperature of 39C (103F). H er skin is warm
o f th e m o s t p ro m in e n t m a n ife s ta tio n s o f th e and ushed, her pulse is 120 beats per minute,
a cu te -p h a s e re s p o n s e , e s p e cia lly if in a m m a tio n and her respirations are shallow and rapid at
is ca u s e d b y in fe ctio n . It is p ro d u ce d in 32 breaths per minute. H er mother states that she
has complained of a sore throat and has refused to
re s p o n s e to p yro g e n s th a t a ct b y p ro m p tin g th e
drink or take medications to bring her fever down.
re le a s e o f p ro s ta g la n d in E2 o r fe ve r-p ro d u cin g
cyto kin e s , w h ich in tu rn re s e ts th e hyp o th a la m ic A. Explain the physiologic mechanisms of fever
th e rm o re g u la to ry ce n te r. generation.
B. Are the warm and ushed skin, rapid heart rate,
Th e re a ctio n s th a t o ccu r d u rin g fe ve r and respirations consistent with this level of
co n s is t o f fo u r s ta g e s : a p ro d ro m a l p e rio d fever?
w ith n o n s p e ci c co m p la in ts , s u ch a s m ild C. After receiving an appropriate dose of
h e a d a ch e a n d fa tig u e ; a ch ill, d u rin g w h ich acetaminophen, the child begins to sweat, and
th e te m p e ra tu re ris e s ; a u s h , d u rin g w h ich the temperature drops to 37.2C. Explain the
th e s kin b e co m e s w a rm a n d u s h e d ; a n d a physiologic mechanisms responsible for the drop
d e fe rve s ce n ce s ta g e , w h ich is m a rke d b y th e in temperature.
in itia tio n o f s w e a tin g .
Th e a p p ro a ch to fe ve r in ch ild re n va rie s
d e p e n d in g o n th e a g e o f th e ch ild . In fa n ts a n d
yo u n g ch ild re n h a ve d e cre a s e d im m u n o lo g ic
fu n ctio n a n d a re m o re co m m o n ly in fe cte d w ith REFEREN CES
viru le n t o rga n is m s .
1. M urphy H S. In ammation. In: Rubin E, Strayer D, eds. R ubins
Th e e ld e rly te n d to h a ve a lo w e r b a s e lin e Pathology: Clinicopathologic Foundations of M edicine. 5th ed.
te m p e ra tu re , s o th a t s e rio u s in fe ctio n s m a y g o Philadelphia, PA: Wolters Kluwer H ealth/ Lippincott Williams &
u n re co g n ize d b e ca u s e o f th e p e rce ive d la ck o f a Wilkins; 2012:4782.
s ig n i ca n t fe ve r. 2. Kumar V, Abbas AK, Fausto N , et al. R obbins and Cotran
Basic Pathology. 8th ed. Philadelphia, PA: Saunders Elsevier;
3. Schmid-Schonbein GW. Analysis of in ammation. A nnu R ev
Biom ed Eng. 2006;8:93131.
4. M edzhitov R. O rigin and physiological roles of in ammation.
RE V IE W E X E RC IS E S N ature. 2008;454(24):428435.
5. Szekanecz Z , Koch AE. Vascular endothelium and immune
responses: implications for in ammation and angiogenesis.
1. A 15-year-old boy presents with abdominal pain, R heum D is Clin N orth A m . 2004;30:97114.
a temperature of 38C (100.5F), and an elevated 6. Steinhubl SR. Platelets as mediators of in ammation. H em atol
white blood cell count of 13,000/L, with an O ncol Clin N orth A m . 2007;21:115121.
increase in neutrophils. A tentative diagnosis of 7. Gawaz M , Langer H , M ay AE. Platelets in in ammation and
appendicitis is made. atherogenesis. J Clin Invest. 2005;115(12):33783384.
8. Ricciotti E, Fitzgerald GA. Prostaglandins and in ammation.
A. Explain the signi cance of pain as it relates to A rterioscler T hrom b Vasc Biol. 2011;31(5):9861000.
the in ammatory response. 9. O rmenetti A, Gattorno M . Principles of in ammation for the
B. What is the cause of the fever and elevated pediatrician. Pediatr Clin N orth A m . 2012;59:225243.
white blood cell count? 10. Bachelet I, Levi-Schaffer F, M ekori YA. M ast cells: not only in
C. What would be the preferred treatment for this allergy. Im m unol A llergy Clin N orth A m . 2006;26:407425.
boy? 11. Frenette PS, Wagner DD. Adhesion moleculesparts I and II.
N Engl J M ed. 1996;334(23):15261529.
2. Aspirin and other nonsteroidal anti-in ammatory 12. Bochner BS. Adhesion molecules as therapeutic targets. Im m unol
A llergy Clin N orth A m . 2004;24:615630.
drugs are often used to control the manifestations
13. Stein DM , N ombela-Arrieta C. Chemokine control of
of chronic in ammatory disorders such as arthritis. lymphocyte traf cking: a general review. Im m unology.
A. Explain their mechanism of action in terms of 2005;116:112.
controlling the in ammatory response. 14. Underhill DM , O zinsky A. Phagocytosis of microbes. A nnu R ev
Im m unol. 2002;20:825852.
15. Simmons DL, Botting RM , H la T. Cyclooxygenase isoenzymes:
3. Persons with long-standing ulcerative colitis, an the biology of prostaglandin synthesis and inhibition. Pharm acol
in ammatory bowel disease, have a higher risk of R ev. 2004;56(3):387437.
colorectal cancer than the general population. 16. Barnes PJ. H ow corticosteroids control in ammation: Q uintiles
Prize Lecture 2005. Br J Pharm acol. 2006;14B:245254.
A. H ypothesize on cancer-producing mechanisms
17. Covington M B. O mega-3 fatty acids. A m Fam Physician.
of this chronic in ammatory disease. 2004;70(1):133140.

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70 U N I T 1 Cell and Tissue Function

18. H arper CR, Jacobson TA. Usefulness of omega-3 fatty acids 35. Blatteis CM , Li S, Li Z , et al. Cytokines, PGE2 , and endotoxic
and prevention of coronary heart disease. A m J Cardiol. fever: a re-assessment. Prostaglandins O ther L ipid M ediat.
2005;96:15211529. 2005;76:118.
19. Gosain A, Gamelli RL. A primer on cytokines. J Burn Care 36. Thompson H J, Pinto-M artin J, Bullock M R. N eurogenic fever
R ehabil. 2005;26:712. after traumatic brain 2011 injury: an epidemiological study.
20. Charo I, Ransohoff RM . The many roles of chemokines J N eurol N eurosurg Psychiatry. 2003;74:614619.
and chemokine receptors in in ammation. N Engl J M ed. 37. O goina D. Fever, fever patterns and 2011 diseases called
2006;354(6):610621. fever A review. J Infect Public H ealth 2011;4(3):108124.
21. Serhan CN , Savill J. Resolution of in ammation: the beginning 38. Patel R, Gallagher JC. Drug fever. Pharm acotherapy.
programs the end. N at Im m unol. 2005;6(12):11911197. 2010;30(1):5769.
22. Serhan CN , Brain SD, Buckley CD, et al. Resolution of 39. Graves RC, O ehler K, Tingle LE. Febrile seizures:
in ammation: state of the art, de nitions and terms. FA SEB J. risks, evaluation, and prognosis. A m Fam Physician.
2007;21:325332. 2012;85(2):149153.
23. Schottenfeld D, Beebe-Dimmer J. Chronic in ammation: 40. Cunha BA. Fever of unknown origin: clinical overview of
a common and important factor in the pathogenesis of neoplasia. and classic and current concepts. Infect D is Clin N orth A m .
CA Cancer J Clin. 2006;56:6983. 2007;21:867915.
24. N athan C. Epidemic in ammation: pondering obesity. M ol M ed. 41. H orowitz H W. Fever of unknown origin or fever of too many
2008;7(8):485492. origins. N Engl J M ed. 2013;368(3):197199.
25. Tateya S, Kim F, Tamori Y. Recent advances in obesity- 42. H amilton JL, John SP. Evaluation of fever in infants and young
related in ammation and insulin resistance. Front Endocrinol children. A m Fam Physician. 2013;87(4):254260.
(L ausanne). 2013;4:93. 43. Ishimine P. Fever without source in children 0 to 36 months of
26. Greenberg AS, O bin M S. O besity and the role of adipose age. Pediatr Clin N orth A m . 2006;53:167194.
tissue in in ammation and metabolism. A m J Clin N utr. 44. ACEP Clinical Policy Committee and Clinical Policies
2006;83(suppl):461S465S. Subcommittee on Pediatric Care. Clinical policy for children less
27. Ridker PM . C-reactive protein, in ammation, and cardiovascular than 3 years presenting to the emergency department with fever.
disease. Curr Issues Cardiol. 2005;32(3):384386. A nn Em erg M ed. 2003;42(4):530545.
28. Ridker PM . H igh-sensitivity C-reactive protein: potential 45. Woolery WA, Franco FR. Fever of unknown origin: keys
adjunct for global risk assessment in primary prevention of to determining the etiology in older patients. G eriatrics.
cardiovascular disease. Circulation. 2001;103:18131818. 2004;59(10):4145.
29. Pearson TA, M ensah GA, Alexander RW, et al. M arkers 46. N orman DC, Wong M G, Yoshikawa TT. Fever of unknown
of in ammation and cardiovascular disease: application to origin in older persons. Infect D is Clin N orth A m .
clinical and public health practice: a statement for healthcare 2007;21:937945.
professionals from the Centers for Disease Control and 47. O utzen M . M anagement of fever in older adults. J G erontol
Prevention and the American H eart Association. Circulation. N urs. 2009;35(5):1723.
30. H otchiss RS, Karl IE. The pathophysiology and treatment of
sepsis. N Engl J M ed. 2003;348(2):138150.
31. H all JE. G uyton and H all Tex tbook of M edical Physiology. 12th
Po rth Es s en tia ls Re s ources
ed. Philadelphia, PA: Saunders Elsevier; 2011:867877.
32. Wilzmann FA. The regulation of body temperature. In: Rhoades Explore the se additional re source s to e nhance le arning
RA, Bell DR. M edical Physiology. 2nd ed. Philadelphia, for this chapte r:
PA: Wolters Kluwer H ealth/Lippincott Williams & Wilkins; NCLEX-Style Que stions and Othe r Re source s
2013:550574. on , http://the Point.lw w.com/PorthEsse ntials4e
33. Roth J, Rummel C, Barth SW, et al. M olecular aspects of fever Study Guide for Esse ntials of Pathophysiology
and hyperthermia. N eurol Clin. 2006;24:421439. Conce pts in Action Animations
34. Blatteis CM . Endotoxic fever: new concepts of its regulation Adaptive Le arning | Powe re d by Pre pU, http://the point.lw w.com/
suggest new approaches to its management. Pharm acol T her.
pre pu

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Cell Prolifera tion a nd Tissue Regenera tion
Cell Prolifera tion Versus Differentia tion
The Cell Cycle
Prolifera tive Ca pa city of Tissues
Stem Cells
In uence of Growth Fa ctors
C h a p t e r
Extra cellula r Ma trix a nd CellMa trix Intera ctions
Hea ling by Connective Tissue Repa ir Ce ll P ro life r a t io n
a n d Tis s u e
Pha ses of Repa ir
Angiogenesis a nd Ingrowth of Gra nula tion
Emigra tion of Fibrobla sts a nd Deposition of
Extra cellula r Ma trix
Re g e n e r a t io n
Ma tura tion a nd Remodeling of the Fibrous
Tissue a n d Re p a ir
Cuta neous Wound Hea ling
Hea ling by Prima ry a nd Seconda ry Intention
Pha ses of Hea ling
Fa ctors Tha t Affect Wound Hea ling
N utritiona l Sta tus
Blood Flow a nd O xygen Delivery
T issue repair, which overlaps the in ammatory pro-
cess that was discussed in Chapter 3, refers to the
restoration of tissue structure and function after an
Impa ired In a mma tory a nd Immune Responses injury. Tissue repair can take the form of regeneration,
Infection, Wound Sepa ra tion, a nd Foreign in which injured cells are replaced with cells of the same
Bodies type, sometimes leaving no residual trace of previous
Wound Hea ling in the Elderly injury; or it can take the form of replacement by con-
nective ( brous) tissue, which leads to scar formation
or brosis in organs such as the liver or lung. For many
types of common injuries, both regeneration and con-
nective tissue replacement contribute to tissue repair.
This chapter is divided into two parts. The rst part dis-
cusses cell proliferation and regeneration, the cell cycle,
the role of stem cells, growth factors, and the extracel-
lular matrix in tissue renewal. The second focuses on
connective tissue repair, cutaneous wound healing, fac-
tors that affect wound healing, and the effect of aging
on wound healing.

C e ll P ro lif e r a t io n a n d Tis s u e
Re g e n e r a t io n
Tissue repair involves the proliferation of various cells,
and close interactions between cells and the extracel-
lular matrix (ECM ). Body organs and tissues are com-
posed of two types of tissues: parenchymal and stromal.
The parenchymal tissues consist of the functioning cells
of an organ or body part: whereas, the stromal tissues
contain the supporting connective tissues, blood vessels,
broblasts, nerve bers, and extracellular matrix.

C e ll P ro lif e r a t io n Ve r s u s
D iff e r e n t ia t io n
Cell proliferation refers to the process of increasing
cell numbers by mitotic division. Cell differentiation is
the process whereby a cell becomes more specialized in


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72 U N I T 1 Cell and Tissue Function

Tis s ue cells, that can differentiate into the different cell types
s te m ce ll throughout life.

Th e C e ll Cyc le
Diffe re ntia tion
In order to understand cell proliferation, whether physi-
ologic (as in tissue regeneration and repair) or patho-
logic (as in cancer), it is important to learn about the
cell cycle, an orderly sequence of events in which a cell
duplicates its genetic contents and divides. During the
cell cycle, the duplicated chromosomes are appropri-
ately aligned for distribution between two genetically
Ce ll prolife ra tion Ce ll popula tion Apoptos is identical daughter cells.
The cell cycle is divided into four distinct phases
FIG U RE 4 -1. In n o rm a l tis s u e s , th e s ize o f th e ce ll p o p u la tio n
is d e te rm in e d b y a b a la n ce o f ce ll p ro life ra tio n , d e a th b y
referred to as G 1 , S, G 2 , and M . Gap 1 (G 1 ) is the post-
a p o p to s is , a n d e m e rg e n ce o f n e w ly d iffe re n tia te d ce lls fro m mitotic phase during which deoxyribonucleic acid
s te m ce lls . (DN A) synthesis ceases while ribonucleic acid (RN A)
and protein synthesis and cell growth take place (see
Understanding the Cell Cycle).14 During the S phase,
terms of structure and function. 1,2 Stem cells are undif- DN A synthesis occurs, giving rise to two separate sets
ferentiated cells that have the capacity to generate mul- of chromosomes, one for each daughter cell. G 2 is the
tiple cell types (to be discussed). In normal tissue the premitotic phase and is similar to G 1 in that DN A syn-
size of the cell population is determined by a balance of thesis ceases while RN A and protein synthesis continue.
cell proliferation, death by apoptosis (see Chapter 2), Collectively, G 1 , S, and G 2 are referred to as interphase.
and emergence of newly differentiated cells from stem The M phase is the phase of nuclear division and cyto-
cells2 (Fig. 4-1). Several cell types proliferate during tis- kinesis. Continually dividing cells, such as the strati ed
sue repair including remnants of injured parenchymal squamous epithelium of the skin, continue to cycle from
tissue cells, vascular endothelial cells, and broblasts. one mitotic division to the next. When environmental
The proliferation of these cell types is driven by proteins conditions are adverse, such as nutrient or growth fac-
called grow th factors. The production of growth fac- tor unavailability, or cells become terminally differenti-
tors and the ability of these cells to respond and expand ated (i.e., highly specialized), cells may exit the cell cycle,
in suf cient numbers are important determinants of the becoming mitotically quiescent and reside in a special
repair process. resting state known as G 0 . Cells in G 0 may reenter the
All of the different cell types in the body originate cell cycle in response to extracellular nutrients, growth
from a single cellthe fertilized ovum. As the embry- factors, hormones, and other signals such as blood loss
onic cells increase in number, they differentiate, facili- or tissue injury that trigger cell renewal. H ighly special-
tating the development of all the different cells and ized and terminally differentiated cells, such as neurons,
organs of the body. The process of differentiation is may permanently stay in G 0 .
regulated by a combination of internal processes involv- Within the cell cycle are checkpoints where pauses or
ing the expression of speci c genes and external stimuli arrests can be made if the speci c events in the phases
provided by neighboring cells, the ECM , and a variety of the cell cycle have not been completed. There are also
of growth factors. The process occurs in orderly steps, opportunities for ensuring the accuracy of DN A repli-
with each progressive step being exchanged for a loss cation. These DN A damage checkpoints allow for any
of ability to develop different cell characteristics. As a defects to be edited and repaired, thereby ensuring that
cell becomes more highly specialized, the stimuli that are each daughter cell receives a full complement of genetic
able to induce mitosis become more limited. N eurons, information, identical to that of the parent cell. 13
which are highly specialized cells, lose their ability to The cyclins are a family of proteins that control the
proliferate once development of the nervous system is entry and progression of cells through the cell cycle. 14
complete. In other, less-specialized tissues, such as the Cyclins bind to (thereby activating) proteins called
skin and mucosal lining of the gastrointestinal tract, a cyclin-dependent k inases (CDKs). Kinases are enzymes
high degree of cell renewal continues throughout life. that phosphorylate proteins. The CDKs phosphorylate
Even in these continuously renewing cell populations, speci c target proteins and are expressed continuously
the more specialized cells are unable to divide. M any during the cell cycle but in an inactive form, whereas the
of these cell populations rely on progenitor or parent cyclins are synthesized during speci c phases of the cell
cells of the same lineage. Progenitor cells are suf ciently cycle and then degraded once their task is completed.
differentiated so that their daughter cells are limited to Different arrangements of cyclins and CDKs are associ-
the same cell line, but they have not reached the point ated with each stage of the cell cycle. For example, cyclin
of differentiation that precludes the potential for active B and CDK1 control the transition from G 2 to M . As
proliferation. Some cell populations have self-renewing the cell moves into G 2 , cyclin B is synthesized and binds
multipotent stem cells, such as the epithelial stem to CDK1. The cyclin BCDK1 complex then directs the

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C H A P T E R 4 Cell Proliferation and Tissue Regeneration and Repair 73

events leading to mitosis, including DN A replication and

assembly of the mitotic spindle. Although each phase of
Dividing s te m ce ll
the cell cycle is monitored carefully, the transition from
G 2 to M is believed to be one of the most important
checkpoints in the cell cycle. In addition to the synthesis S te m ce ll P roge nitor ce ll
and degradation of the cyclins, the cyclinCDK com-
plexes are regulated by the binding of CDK inhibitors. Da ughte r ce lls
The CDK inhibitors are particularly important in regu-
lating cell cycle checkpoints during which mistakes in
DN A replication are repaired. The nding that the cell
cycle can be reactivated by removing CDK inhibitors in
quiescent and nonproliferating cells has potential impli-
cations for tissue repair and cell replacement therapy.4
Diffe re ntia te d ce lls

P ro lif e r a t ive C a p a c it y o f Tis s u e s

FIG U RE 4 -2 . Me ch a n is m s o f s te m ce llm e d ia te d ce ll
The capacity for regeneration varies with the tissue re p la ce m e n t. Divis io n o f a s te m ce ll w ith a n u n lim ite d p o te n tia l
and cell type. Body tissues are divided into three types fo r p ro life ra tio n re s u lts in o n e d a u g h te r ce ll, w h ich re ta in s
depending on the ability of their cells to undergo regen- th e ch a ra cte ris tics o f a s te m ce ll, a n d a s e co n d d a u g h te r ce ll
eration: (1) continuously dividing, (2) stable, and (3) th a t d iffe re n tia te s in to a p ro g e n ito r o r p a re n t ce ll, w ith lim ite d
p o te n tia l fo r d iffe re n tia tio n a n d p rolife ra tio n . As th e d a u g h te r
permanent tissues.1,2
ce lls o f th e p ro g e n ito r ce ll p ro life ra te th e y b e co m e m o re
Continuously dividing or labile tissues are those in d iffe re n tia te d , u n til th e y re a ch th e s ta g e w h e re th e y a re fu lly
which the cells continue to divide and replicate through- d iffe re n tia te d .
out life, replacing cells that are continually being
destroyed. They include the surface epithelial cells of
the skin, oral cavity, vagina, and cervix; the columnar
epithelium of the gastrointestinal tract, uterus, and fal- generated from stem cells. Stem cells are reserve cells that
lopian tubes; the transitional epithelium of the urinary remain quiescent until there is a need for cell replenish-
tract; and bone marrow cells. These tissues can readily ment, in which case they divide, producing other stem
regenerate after injury as long as a pool of stem cells is cells and cells that can carry out the functions of the dif-
preserved. Bleeding, for example, stimulates the rapid ferentiated cell. When a stem cell divides, one daughter
proliferation of replacement cells by the blood-forming cell retains the stem cell characteristics, and the other
progenitor cells of the bone marrow. daughter cell becomes a progenitor cell that undergoes a
Stable tissues contain cells that normally stop divid- process that leads to terminal differentiation (Fig. 4-2).
ing when growth ceases. Cells in these tissues remain Stem cells are characterized by three important prop-
quiescent in the G 0 stage of the cell cycle. H owever, erties: self-renewal, asymmetric replication, and differ-
these cells are capable of undergoing regeneration when ential potential.1,2 Self-renew al means that the stem cells
confronted with an appropriate stimulus; thus, they can undergo numerous mitotic divisions while main-
are capable of reconstituting the tissue of origin. Stable taining an undifferentiated state. A sym m etric replica-
cells constitute the parenchyma of solid organs such as tion means that after each cell division, some progeny of
the liver and kidney. They also include smooth muscle the stem cell enter a differentiation pathway, while oth-
cells, vascular endothelial cells, and broblasts, the pro- ers remain undifferentiated, retaining their self-renewal
liferation of which is particularly important to wound capacity. The progeny of each progenitor cell follows a
healing. more restricted genetic program, with the differentiating
The cells in perm anent tissues do not proliferate. cells undergoing multiple mitotic divisions in the process
The cells in these tissues are considered to be terminally of becoming a more mature cell type, and with each gen-
differentiated and do not undergo mitotic division in eration of cells becoming more specialized. In this way, a
postnatal life. The permanent cells include nerve cells, single stem cell can give rise to the many cells needed for
skeletal muscle cells, and cardiac muscle cells. These normal tissue repair or blood cell production.
cells do not normally regenerate; once destroyed, they The term potency is used to de ne the differentia-
are replaced with brous scar tissue that lacks the func- tion potential of stem cells. Totipotent stem cells are
tional characteristics of the destroyed tissue. those produced by a fertilized ovum. The rst few cells
produced after fertilization are totipotent and can dif-
ferentiate into embryonic and extraembryonic cells.
S t e m C e lls Totipotent stem cells give rise to pluripotent stem cells
that can differentiate into the three germ layers of the
Another type of tissue cell, called a stem cell, remains embryo. M ultipotent stem cells are cells such as hema-
incompletely differentiated throughout life.1,2,5 In most topoietic stem cells that give rise to a family of cells,
continuously dividing tissues, the mature cells are ter- including the red blood cells and all the various types
minally differentiated and short lived. As mature cells of leukocytes. Finally, unipotent stem cells produce only
die the tissue is replenished by the differentiation of cells one cell type but retain the property of self-renewal.
(tex t continues on page 76)

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74 U N I T 1 Cell and Tissue Function

U N D E R S TA N D IN G Th e Ce ll Cy cle
A cell reproduces by perform ing an orderly sequence of events called the cell cycle.
The cell cycle is divided into four phases of unequal duration that include the (1)
synthesis (S) and m itosis (M) phases that are separated by (2) two gaps (G 1 and G 2).
There is also (3) a dorm ant phase (G 0) during which the cell m ay leave the cell cycle.
Movem ent through each of these phases is m ediated at (4) speci c checkpoints that
are controlled by speci c enzym es and proteins called cyclins.

S y n t h e s is and M it o s is .
Synthesis (S) and mitosis (M ) rep-
resent the two major phases of
the cell cycle. The S phase, which
takes about 10 to 12 hours, is the
period of DN A synthesis and repli- S
cation of the chromosomes. The M
phase, which usually takes less than
an hour, involves formation of the G1
mitotic spindle and cell division with
formation of two daughter cells.

G0 M

Ga p s 1 a n d 2 . Because most cells
require time to grow and double
their mass of proteins and organ- S
elles, extra gaps (G) are inserted into
the cell cycle. G 1 is the stage during G1
which the cell is starting to prepare
for DN A replication and mitosis
through protein synthesis and an G2
increase in organelle and cytoskel-
etal elements. G 2 is the premitotic
phase. During this phase, enzymes G0 M
and other proteins needed for cell
division are synthesized and moved
to their proper sites.

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C H A P T E R 4 Cell Proliferation and Tissue Regeneration and Repair 75

Ga p 0 . G 0 is the stage after mito- S
sis during which a cell may leave the
cell cycle and either remain in a state
of inactivity or reenter the cell cycle G1
at another time. Labile cells, such as
blood cells and those that line the S ta ble ce lls
gastrointestinal tract, do not enter (e .g., G2
he pa tocyte s )
G 0 but continue cycling. Stable cells,
such as hepatocytes, enter G 0 after
mitosis but can reenter the cell cycle M
when stimulated by the loss of other G0
cells. Permanent cells, such as neu-
rons that become terminally differ-
entiated after mitosis, leave the cell Pe rma ne nt ce lls
(e .g., ne rve s )
cycle and are no longer capable of
cell renewal.

G 1 /S che ckpoint
4 (che cks for DNA da ma ge )
Ch e c k p o in t s a n d Cy c lin s . In
most cells there are several check-
points in the cell cycle, at which time
the cycle can be arrested if previous
events have not been completed. For S
example, the G 1 /S checkpoint moni-
tors whether the DN A in the chro- Cyclin E
mosomes is damaged by radiation G1 Cyclin A
or chemicals, and the G 2 /M check-
point prevents entry into mitosis if
DN A replication is not complete. Cyclin B G2
The cyclins are a family of pro-
teins that control entry and progres-
sion of cells through the cell cycle. M
They function by activating pro-
teins called cyclin-dependent kinases G0
(CDKs). Different combinations of G 2 /M che ckpoint
(che cks for da ma ge d
cyclins and CDKs are associated or unduplica te d DNA)
with each stage of the cell cycle. In
addition to the synthesis and deg-
radation of the cyclins, the cyc-
linCDK complexes are regulated
by the binding of CDK inhibitors.
The CDK inhibitors are particularly
important in regulating cell cycle
checkpoints during which mistakes
in DN A replication are repaired.

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76 U N I T 1 Cell and Tissue Function

(tex t continued from page 73)

In recent years, it has become useful to categorize to small proteins that increase cell size and cell division. 2
stem cells into two basic categories: embryonic and adult In addition to cell proliferation, most growth factors
stem cells. 1,2,5,6 Embryonic stem cells are pluripotent cells have other effects. They assist in regulating the in amma-
derived from the inner cell mass of the blastocyst stage tory process; serve as chemoattractants for neutrophils,
of the embryo. These pluripotent stem cells have the monocytes (macrophages), broblasts, keratinocytes,
capacity to generate multiple cell lines. As mentioned and epithelial cells; stimulate angiogenesis; and contrib-
earlier, unipotential stem cells are normally present in ute to the generation of the ECM . Some growth factors
proliferative tissues and generate cell lineages speci c stimulate the proliferation of some cells and inhibit the
to that tissue. It is now recognized, however, that stem cycling of other cells. In fact, a growth factor can have
cells with the capacity to generate multiple lineages are opposite effects on the same cell depending on its chang-
present in the bone marrow and several other tissues of ing concentration during the healing process.
adult individuals. These cells are called adult stem cells M any of the growth factors are produced by leuko-
or tissue stem cells. Whether adult stem cells have a dif- cytes recruited to the site of injury or activated at the
ferentiation capacity similar to that of embryonic stem site by the in ammatory process. O ther growth factors
cells remains the subject of current debate and research. 2 are produced by parenchymal cells or stromal cells in
Thus far, bone marrow stem cells have been shown to response to injury or loss. Growth factors are named for
have very broad differentiation capabilities, being able their tissue of origin (e.g., platelet-derived growth fac-
to generate not only blood cells, but also fat, cartilage, tor [PDGF], broblast growth factor [FGF]), their bio-
bone, endothelial, and muscle cells. logic activity (e.g., transforming growth factor [TGF]),
A new eld of medicineregenerative m edicineis or the cells on which they act (e.g., vascular endothelial
mainly concerned with the regeneration and restora- growth factor [VEGF]). The sources and functions of
tion of damaged organs using embryonic and adult stem selected growth factors are described in Table 4-1.
cells. 2,6,7 O ne of the most exciting prospects in this area The signaling pathways for the growth factors are
is a type of stem cell therapy known as therapeutic clon- similar to those of other cellular receptors that recognize
ing. O ther potential therapeutic strategies that use stem extracellular ligands. The binding of a growth factor to
cells involve the transplantation of stem cells into areas its receptor triggers a series of events by which extra-
of injury, mobilization of stem cells from the bone mar- cellular signals are transmitted into the cell, leading to
row into injured tissues, and use of stem cell culture the stimulation or inhibition of gene expression. These
systems to produce large amounts of differentiated stem genes typically have several functionsthey relieve
cells for transplantation into injured tissue. blocks on cell cycle progression (thus promoting cell
proliferation), prevent apoptosis, and enhance synthesis
of cellular proteins in preparation for mitosis. Signaling
may occur in the cell producing the growth factor (auto-
In u e n c e o f G ro w t h Fa c t o r s crine signaling), in cells in the immediate vicinity of the
Cell proliferation can be triggered by chemical media- cell releasing the growth factor (paracrine signaling), or
tors including growth factors, hormones, and cyto- in distant target cells through growth factors that are
kines. 1,2,811 The term grow th factor is generally applied released into the bloodstream (endocrine signaling).

TA BLE 4 - 1 Grow th Facto rs Invo lve d in Tis s ue Re ge ne ratio n and Wo und He aling
G ro w t h Fa c t o r S o u rc e Fu n c t io n

Ep id e rm a l g ro w th fa cto r Activa te d m a cro p h a g e s , ke ra tin o cyte s , Mito g e n ic fo r ke ra tin o cyte s a n d b ro b la s ts ; s im u la te s

(EGF) a n d m a ny o th e r ce lls ke ra tin o cyte m ig ra tio n a n d g ra n u la tio n tis s u e fo rm a tio n
Tra n s fo rm in g g ro w th Activa te d m a cro p h a g e s , T lym p h o cyte s , S im ila r to EGF; s tim u la te s re p lica tio n o f h e p a to cyte s a n d
fa cto r- (TGF-) ke ra tin o cyte s , a n d m a ny o th e r ce lls m a ny e p ith e lia l ce lls
Tra n s fo rm in g g ro w th Pla te le ts , m a cro p h a g e s , T lym p h o cyte s , Ch e m o ta ctic fo r n e u tro p h ils , m a cro p h a g e s , b ro b la s ts ,
fa cto r- (TGF-) ke ra tin o cyte s , s m o o th m u s cle ce lls , a n d s m o o th m u s cle ce lls ; s tim u la te s a n g io g e n e s is
b ro b la s ts a n d p ro d u ctio n o f b ro u s tis s u e ; in h ib its p ro te in a s e
p ro d u ctio n a n d ke ra tin o cyte p ro life ra tio n
Va s cu la r e n d o th e lia l ce ll Me s e n chym a l ce lls In cre a s e s va s cu la r p e rm e a b ility; m ito g e n ic fo r e n d o th e lia l
g ro w th fa cto r (VEGF) ce lls o f b lo o d ve s s e ls
Pla te le t-d e rive d g ro w th Pla te le ts , m a cro p h a g e s , e n d o th e lia l Ch e m o ta ctic fo r n e u tro p h ils , m a cro p h a g e s , b ro b la s ts ,
fa cto r (PDGF) ce lls , ke ra tin o cyte s , s m o o th m u s cle a n d s m o o th m u s cle ce lls ; s tim u la te s p ro d u ctio n o f
ce lls p ro te in a s e s , b ro n e ctin , a n d hya lu ro n ic a cid ; s tim u la te s
a n g io g e n e s is a n d w o u n d re m o d e lin g
Fib ro b la s t g ro w th fa cto r Ma cro p h a g e s , m a s t ce lls , T Ch e m o ta ctic fo r b ro b la s ts ; m ito g e n ic fo r b ro b la s ts
(FGF) lym p h o cyte s , e n d o th e lia l ce lls , a n d ke ra tin o cyte s ; s tim u la te s a n g io g e n e s is , w o u n d
b ro b la s ts , a n d m a ny o th e r tis s u e s co n tra ctio n , a n d m a trix d e p o s itio n
Ke ra tin o cyte g ro w th Fib ro b la s ts S tim u la te s ke ra tin o cyte m ig ra tio n , p ro life ra tio n , a n d
fa cto r (KGF) d iffe re n tia tio n

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C H A P T E R 4 Cell Proliferation and Tissue Regeneration and Repair 77

There is continued interest in developing growth factors is involved in the regulation of growth, movement, and
as a means of increasing cell proliferation and enhanc- differentiation of the cells surrounding it; and it provides
ing wound healing as well as developing strategies to for the storage and presentation of regulatory molecules
block growth factor signaling pathways that could be that control the repair process. The ECM also provides
used to inhibit malignant cell proliferation in cancer. the scaffolding for tissue renewal. Although the cells in
many tissues are capable of regeneration, injury does
not always result in restoration of normal structure
Ex t r a c e llu la r M a t r ix a n d C e llM a t r ix unless the ECM is intact. The integrity of the underly-
In t e r a c t io n s ing basement membrane, in particular, is critical to the
regeneration of tissue. When the basement membrane is
The understanding of tissue regeneration and repair has disrupted, cells proliferate in a haphazard way, resulting
expanded over the past several decades to encompass the in disorganized and nonfunctional tissues.
complex environment of the ECM . There are two basic Critical to the process of wound healing are transi-
forms of ECM : (1) the basem ent m em brane, which sur- tions in the composition of the ECM . In the transitional
rounds epithelial, endothelial, and smooth muscle cells; process, the ECM components are degraded by prote-
and (2) the interstitial m atrix , which is present in the ases (enzymes) that are secreted locally by a variety of
spaces between cells in connective tissue and between cells ( broblasts, macrophages, neutrophils, synovial
the epithelium and supporting cells of blood vessels. cells, and epithelial cells). Some of the proteases, such
The ECM is secreted locally and assembles into a net- as the collagenases, are highly speci c, cleaving particu-
work of spaces surrounding tissue cells (see Chapter 1). lar proteins at a small number of sites. 10,11 This allows
There are three basic components of the ECM : brous for the structural integrity of the ECM to be retained
structural proteins (e.g., collagen and elastin bers), while healing occurs. Because of their potential to pro-
water-hydrated gels (e.g., proteoglycans and hyaluronic duce havoc in tissues, the actions of the proteases are
acid) that permit resilience and lubrication, and adhe- tightly controlled. They are typically produced in an
sive glycoproteins (e.g., bronectin, laminin) that con- inactive form that must rst be activated by certain
nect the matrix elements to one another and to cells13,9 chemicals likely to be present at the site of injury, and
(Fig. 4-3). Integrins are a family of transmembrane gly- they are rapidly inactivated by tissue inhibitors. Recent
coproteins that are the main cellular receptors for ECM research has focused on the unregulated action of the
components such as bronectin and laminin. They bind proteases in disorders such as cartilage matrix break-
to many ECM components, initiating signaling cas- down in arthritis and neuroin ammation in multiple
cades that affect cell proliferation and differentiation. sclerosis. 11
Fibroblasts, which reside in close proximity to collagen
bers, are responsible for the synthesis of collagen, elas-
tic, and reticular bers, and complex carbohydrates in
the ground substance.
The ECM provides turgor to soft tissue and rigidity
to bone; it supplies the substratum for cell adhesion; it S U M M A R Y C O N C EP TS

Th e p ro ce s s o f tis s u e g ro w th a n d re p a ir invo lve s

Colla ge n p ro life ra tio n o f fu n ctio n in g p a re n chym a l ce lls
P rote oglyca n o f a n o rga n o r b o d y p a rt a n d its s u p p o rtin g
Fibrobla s t co n n e ctive tis s u e s a n d e xtra ce llu la r m a trix.
Hya luronic
a cid Ce ll p ro life ra tio n re fe rs to th e p ro ce s s o f
in cre a s in g ce ll n u m b e rs b y m ito tic d ivis io n .
Ce ll d iffe re n tia tio n is th e p ro ce s s w h e re b y
a ce ll b e co m e s m o re s p e cia lize d in te rm s o f
s tru ctu re a n d fu n ctio n . Th e p e rio d ic b io ch e m ica l
a n d s tru ctu ra l e ve n ts o ccu rrin g d u rin g ce ll
p ro life ra tio n a re ca lle d th e ce ll cycle .
Fibrone ctin
Bo d y ce lls a re d ivid e d in to typ e s a cco rd in g to
th e ir a b ility to re g e n e ra te . La b ile ce lls , s u ch a s
th e e p ith e lia l ce lls o f th e s kin a n d ga s tro in te s tin a l
tra ct, a re th o s e th a t co n tin u e to re g e n e ra te
Inte grin Ce ll th ro u g h o u t life . S ta b le ce lls , s u ch a s th o s e in th e
me mbra ne live r, a re th o s e th a t n o rm a lly d o n o t d ivid e b u t a re
ca p a b le o f re g e n e ra tio n w h e n co n fro n te d w ith a n
FIG U RE 4 -3 . Co m p o n e n ts o f th e e xtra ce llu la r m a trix a n d a p p ro p ria te s tim u lu s . Pe rm a n e n t o r xe d ce lls a re
s u p p o rtin g co n n e ctive tis s u e co m p o n e n ts invo lve d in tis s u e
re p a ir.
(co n tin u e d )

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78 U N I T 1 Cell and Tissue Function

S U M M A R Y C O N C E P T S (co n tin u e d )
th o s e th a t a re u n a b le to re g e n e ra te . S te m ce lls
a re u n d iffe re n tia te d ce lls o f co n tin u o u s ly d ivid in g
tis s u e s th a t h a ve th e ca p a city to g e n e ra te
m u ltip le ce ll typ e s .
Tis s u e re g e n e ra tio n a n d re p a ir a re m e d ia te d
b y grow th fa ctors tha t incre a se ce ll size , ce ll
d ivisio n, a nd ce ll d iffe re n tia tion, a nd e nha nce
the p roduction o f spe cia lize d e xtra ce llula r m a trix
(ECM) p rote ins by ce lls such a s bro bla s ts. Am on g
its m a ny fu n ctio n s , th e ECM a id s in th e re g u la tio n
o f ce ll prolife ra tion, m ove m e nt, a nd diffe re ntia tion
d urin g w oun d re pa ir by p roviding a fo unda tion for
ce ll a d h e s io n a n d a re s e rvo ir fo r g ro w th fa cto rs .

He a lin g b y C o n n e c t ive Tis s u e

Re p a ir
The primary objective of the healing process is to ll
the gap created by tissue destruction and to restore the
structural continuity of the injured part. Tissue regen-
eration refers to the restoration of injured tissue to its
normal structure and function by proliferation of adja-
cent surviving cells. As discussed earlier in the chapter,
cell renewal occurs continuously in labile tissues such as
gastrointestinal epithelium and skin. Regeneration can
also occur in parenchymal organs with stable cell popu-
lations but, with the exception of the liver, is usually a
FIG U RE 4 -4 . Orga n ize d s tra n d s o f co lla g e n (a rro w s ) in
limited process. It should be pointed out that extensive co n s trictive p e rica rd itis . (Fro m Se p h a l GC, Da vid s o n J M.
regeneration can occur only if the residual tissue is struc- Re p a ir, re g e n e ra tio n , a n d b ro s is . In : Ru b in R, S tra ye r DS , e d s .
turally and functionally intact. If the tissue is damaged Ru b ins Pa th o lo g y: Clin ico p a th o lo g ic Fo u n d a tio n s o f Me d icin e .
by infection or in ammation, regeneration is incomplete 6th e d . Ph ila d e lp h ia , PA: Wo lte rs Klu w e r He a lth | Lip p in co tt
and accomplished by replacement with scar tissue. Willia m s & Wilkin s ; 2012:94.)
When regeneration cannot occur, healing by replace-
ment with a connective ( brous) tissue occurs, a process
that terminates in scar formation. The term brosis is often deposition of extracellular matrix; and (3) matura-
used to describe the extensive deposition of collagen that tion and reorganization of the brous tissue (remodel-
occurs in organs that are incapable of regeneration.2 When ing).1,2,1016 It usually begins within 24 hours of injury
this occurs, brous tissue grows into the area of damage, and is evidenced by the migration of broblasts and the
converting it to a mass of brous tissue, a process called induction of broblast and endothelial cell proliferation.2
organization.1,2 It can also occur in serous cavities (pleura, By 3 to 5 days, a special type of tissue called granulation
peritoneum) when excessive exudate accumulates and can- tissue is apparent.2 The granulation tissue then progres-
not be cleared. In the pericardium, broblasts secrete and sively accumulates connective tissue, eventually resulting
organize collagen within brous strands, thereby binding in the formation of a scar, which is then remodeled.
the visceral and parietal pericardia together 1 (Fig. 4-4).
Fibrous strands sometimes become organized within the Ang io ge ne s is and Ing row th o f Granulatio n
peritoneal cavity following abdominal surgery or perito- Tis s ue
nitis. These strands of collagen, called adhesions, can trap Granulation tissue is a glistening red, moist connective
loops of bowel and cause obstruction.1 tissue that lls the injured area while necrotic debris is
removed 1,2 (Fig. 4-5). It is composed of newly formed
P h a s e s o f Re p a ir capillaries, proliferating broblasts, and residual in am-
matory cells. The development of granulation tissue
Repair by connective tissue deposition can be divided into involves the growth of new capillaries (angiogenesis).
three phases: (1) hemostasis, angiogenesis, and ingrowth Angiogenesis is a tightly regulated process that includes
of granulation tissue; (2) emigration of broblasts and migration of endothelial cells to the site of tissue injury,

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C H A P T E R 4 Cell Proliferation and Tissue Regeneration and Repair 79

in two phases: emigration and proliferation of broblasts

into the site of injury, and deposition of extracellular
matrix by these cells. The recruitment and proliferation
of broblasts is mediated by a number of growth factors
including FGF-2 and TGF-. These growth factors are
released from endothelial cells and from in ammatory
cells that are present at the site of injury.
As healing progresses, the number of proliferating
broblasts and formation of new vessels decrease and
there is increased synthesis and deposition of collagen.
Collagen synthesis is important to the development of
A strength in the healing wound site. Ultimately, the gran-
ulation tissue scaffolding evolves into a scar composed
of largely inactive spindle-shaped broblasts, dense col-
lagen bers, fragments of elastic tissue, and other ECM
components. As the scar matures, vascular degeneration
eventually transforms the highly vascular granulation
tissue into a pale, largely avascular scar.

Maturatio n and Re m o de ling o f the

Fibro us Tis s ue
The transition from granulation to scar tissue involves
shifts in the modi cation and remodeling of the ECM .
The outcome of the repair process is, in part, a bal-
ance between previously discussed ECM synthesis and
degradation. The rate of collagen synthesis diminishes
until it reaches equilibrium with collagen degradation.
The degradation of collagen and other ECM proteins
is achieved through a family of metalloproteinases,
which require zinc for their activity. The metallopro-
FIG U RE 4 -5 . Gra n u la tio n tis s u e . (A) A fo o t cove re d b y teinases are produced by a variety of cell types ( bro-
g ra n u la tio n tis s u e . (B) A p h o to m icro g ra p h o f g ra n u la tio n tis s u e blasts, macrophages, synovial cells, and some epithelial
s h o w s th e th in -wa lle d ve s s e ls (a rro w s ) e m b e d d e d in a lo o s e cells), and their synthesis and secretion are regulated
co n n e ctive tis s u e m a trix co n ta in in g m e s e n chym a l ce lls a n d by growth factors, cytokines, and other agents. 10,11
o cca s io n a l in a m m a to ry ce lls . (Fro m Se p h a l GC, Da vid s o n J M. Their synthesis may be suppressed pharmacologically
Re p a ir, re g e n e ra tio n , a n d b ro s is . In : Ru b in R, S tra ye r DS , e d s . by corticosteroids. M etalloproteinases are typically
Ru b ins Pa th o lo g y: Clin ico p a th o lo g ic Fo u n d a tio n s o f Me d icin e . released as inactive precursors that require activation
6th e d . Ph ila d e lp h ia , PA: Wo lte rs Klu w e r He a lth | Lip p in co tt
by enzymes, such as proteases, that are present at sites
Willia m s & Wilkin s ; 2012:94.)
of injury.

formation of capillary buds, and proliferation of endothe-

lial cells, followed by fusion and remodeling of the endo- C u t a n e o u s Wo u n d He a lin g
thelial cells into capillary tubes. Several growth factors
induce angiogenesis, but the most important are VEGF Thus far, this chapter has focused on general aspects of
and basic FGF-2. In angiogenesis, VEGF stimulates both tissue repair and wound healing. The following section
proliferation and motility of endothelial cells, thus initiat- speci cally addresses healing of skin wounds (cutane-
ing the process of capillary sprouting. FGF-2 participates ous wound healing). This is a process that involves both
in angiogenesis mainly by stimulating the proliferation of epithelial cell regeneration and connective tissue scar
endothelial cells. During angiogenesis, new blood vessels formation, and thus is illustrative of general principles
are leaky because of incompletely formed interendothe- that apply to all tissues.
lial cell junctions and because VEGF increases vascu-
lar permeability. This leakiness explains the edematous He aling by Prim ary and S e co ndary Inte ntio n
appearance of granulation tissue and accounts in part for Depending on the extent of tissue loss, wound closure
the swelling that may persist in healing wounds long after and healing occur by primary or secondary intention
the acute in ammation has subsided. (Fig. 4-6). A sutured surgical incision is an example of
Em ig ratio n o f Fibro blas ts and De po s itio n healing by primary intention. Larger wounds (e.g., burns
and large surface wounds) that have a greater loss of
o f Extrace llular Matrix
tissue and contamination heal by secondary intention.
Scar formation builds on the granulation tissue frame- H ealing by secondary intention is slower than healing by
work of new vessels and loose ECM . The process occurs primary intention and results in the formation of larger

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80 U N I T 1 Cell and Tissue Function

remain for an extended period. These cells, arising

from blood monocytes, are essential to the healing
process. Their functions include phagocytosis and
Firs t inte ntion, release of growth factors that stimulate epithelial cell
no tis s ue los s growth, angiogenesis, and attraction of broblasts.
When a large wound occurs in deeper tissues, neu-
trophils and macrophages are required to remove the
debris and facilitate closure. Although a wound may
heal in the absence of neutrophils, it cannot heal in the
absence of macrophages.

Pro life rative Phas e . The proliferative phase of heal-

ing usually begins within 2 to 3 days of injury and may
last as long as 3 weeks in wounds healing by primary
intention. The primary processes during this time focus
on the building of new tissue to ll the wound space.
The key cell during this phase is the broblast. The
broblast is a connective tissue cell that synthesizes and
secretes collagen and other intercellular elements needed
S e cond inte ntion,
tis s ue los s
for wound healing. Fibroblasts also produce numerous
growth factors that induce angiogenesis and endothelial
FIG U RE 4 -6 . He a lin g b y p rim a ry a n d s e co n d a ry in te n tio n . cell proliferation and migration.
As early as 24 to 48 hours after injury, broblasts and
vascular endothelial cells begin proliferating to form the
amounts of scar tissue. A wound that might otherwise granulation tissue that serves as the foundation for scar
have healed by primary intention may become infected tissue development. This tissue is fragile and bleeds eas-
and heal by secondary intention. ily because of the numerous, newly developed capillary
buds. Wounds that heal by secondary intention have
Phas e s o f He aling more necrotic debris and exudate that must be removed,
and they involve larger amounts of granulation tissue.
Cutaneous wound healing is commonly divided into The newly formed blood vessels are leaky and allow
three phases: (1) the in ammatory phase, (2) the prolif- plasma proteins and white blood cells to leak into the
erative phase, and (3) the remodeling phase. 1,2,1719 The tissues.
duration of the phases is fairly predictable in wounds The nal component of the proliferative phase is
healing by primary intention. In wounds healing by sec- epithelialization, which is the migration, proliferation,
ondary intention, the process depends on the extent of and differentiation of the epithelial cells at the wound
injury and the healing environment. edges to form a new surface layer that is similar to that
destroyed by the injury. In wounds that heal by primary
In am m ato ry Phas e . The in ammatory phase of intention, these epithelial cells proliferate and seal the
wound healing begins at the time of injury and is a wound within 24 to 48 hours. Because epithelial cell
critical period because it prepares the wound environ- migration requires a moist vascular wound surface and
ment for healing.18 It includes hemostasis (see Chapter is impeded by a dry or necrotic wound surface, epitheli-
12) and the vascular and cellular phases of in amma- alization is delayed in open wounds until a bed of gran-
tion. H emostatic processes are activated immediately ulation tissue has formed. When a scab has formed on
at the time of injury. There is constriction of injured the wound, the epithelial cells migrate between it and
blood vessels and initiation of blood clotting by way of the underlying viable tissue; when a signi cant portion
platelet activation and aggregation and deposition of of the wound has been covered with epithelial tissue, the
brin. After a brief period of constriction, these same scab lifts off.
vessels dilate and capillaries increase their permeability, At times, excessive granulation tissue, sometimes
allowing plasma and blood components to leak into referred to as proud esh, may form and extend above
the injured area. In small surface wounds, the clot loses the edges of the wound, preventing reepithelialization
uid and becomes a hard, desiccated scab that protects from taking place. Surgical removal or chemical cauter-
the area. ization of the defect allows healing to proceed.
The cellular phase of in ammation follows and is As the proliferative phase progresses, there is con-
evidenced by the migration of phagocytic white blood tinued accumulation of collagen and proliferation of
cells that digest and remove invading organisms, broblasts. Collagen synthesis reaches a peak within 5
brin, extracellular debris, and other foreign matter. to 7 days and continues for several weeks, depending on
The neutrophils arrive within minutes and are usually wound size. By the second week, the white blood cells
gone by day 3 or 4. They ingest bacteria and cellular have largely left the area, the edema has diminished, and
debris. Within 24 to 48 hours, macrophages, which the wound begins to blanch as the small blood vessels
are larger phagocytic cells, enter the wound area and become thrombosed and degenerate.

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C H A P T E R 4 Cell Proliferation and Tissue Regeneration and Repair 81

Re m o de ling Phas e . The third phase of wound heal- predisposed individuals and are more common in
ing, the remodeling process, begins approximately 3 African Americans and other dark skinned people. 1,2,19
weeks after injury and can continue for 6 months or The majority of keloids lead to considerable cosmetic
longer, depending on the extent of the wound. As the defects, but can grow to suf cient size to become symp-
term implies, there is continued remodeling of scar tomatic by causing deformity or limiting joint mobility.
tissue by simultaneous synthesis of collagen by bro- Thus far the majority of keloid research has focused
blasts and lysis by collagenase enzymes. As a result on growth factors and signaling pathways, but unfor-
of these two processes, the architecture of the scar tunately, reliable preventative or treatment measures
becomes reoriented to increase the tensile strength of have yet to be established.
the wound.
M ost wounds do not regain the full tensile strength
of unwounded skin after healing is completed.
Carefully sutured wounds immediately after surgery Fa c t o r s Th a t A ff e c t Wo u n d He a lin g
have approximately 70% of the strength of unwounded Although many local and systemic factors impair heal-
skin, largely because of the placement of the sutures. ing, science has found only a few ways to promote
This allows persons to move about freely after surgery wound repair. Among the causes of impaired wound
without fear of wound separation. When the sutures healing are malnutrition; impaired blood ow and
are removed, usually at the end of the 1st week, wound oxygen delivery; impaired in ammatory and immune
strength is approximately 10% . It increases rapidly responses; infection, wound separation, and foreign
over the next 4 weeks and then slows, reaching a bodies; and age effects.21
plateau of approximately 70% to 80% of the tensile
strength of unwounded skin at the end of 3 months. 2
An injury that heals by secondary intention undergoes Nutritio nal S tatus
wound contraction during the proliferative and remod-
eling phases. As a result, the scar that forms is consid- Successful wound healing depends in part on adequate
erably smaller than the original wound. Cosmetically, stores of proteins, carbohydrates, fats, vitamins, and
this may be desirable because it reduces the size of the minerals. It is well recognized that malnutrition slows
visible defect. H owever, contraction of scar tissue over the healing process, causing wounds to heal inade-
joints and other body structures tends to limit move- quately or incompletely. 22,23 Protein de ciencies prolong
ment and cause deformities. As a result of loss of elas- the in ammatory phase of healing and impair broblast
ticity, scar tissue that is stretched fails to return to its proliferation, collagen and protein matrix synthesis,
original length. angiogenesis, and wound remodeling. Carbohydrates
An abnormality in healing by scar tissue repair are needed as an energy source for white blood cells.
is k eloid formation. 20 Keloids are benign tumor- Carbohydrates also have a protein-sparing effect and
like masses caused by excess production of scar tis- help to prevent the use of amino acids for fuel when
sue (Fig. 4-7). They tend to develop in genetically they are needed for the healing process. Fats are essen-
tial constituents of cell membranes and are needed for
the synthesis of new cells.
Although most vitamins are essential cofactors for
the daily functions of the body, vitamins play an essen-
tial role in the healing process. Vitamin C is needed for
collagen synthesis. In vitamin C de ciency, improper
sequencing of amino acids occurs, proper linking of
amino acids does not take place, the by-products of
collagen synthesis are not removed from the cell, new
wounds do not heal properly, and old wounds may pull
apart. Administration of vitamin C rapidly restores
the healing process to normal. Vitamin A functions in
stimulating and supporting epithelialization, capillary
formation, and collagen synthesis. Vitamin A also has
been shown to counteract the anti-in ammatory effects
of corticosteroid drugs and can be used to reverse these
effects in persons who are on chronic steroid therapy.
The B vitamins are important cofactors in enzymatic
reactions that contribute to the wound-healing process.
All are water soluble and must be replaced daily, with
FIG U RE 4 -7. Ke lo id . A lig h t-s kin n e d b la ck w o m a n w ith ke lo id
th a t d e ve lo p e d a fte r e a r p ie rcin g . (Fro m Se p h a l GC, Da vid s o n
the exception of vitamin B12 , which is stored in the liver
J M. Re p a ir, re g e n e ra tio n , a n d b ro s is . In : Ru b in R, S tra ye r and must be replaced daily. Vitamin K plays an indirect
DS , e d s . Ru b ins Pa th o lo g y: Clin ico p a th o lo g ic Fo u n d a tio n s o f role in wound healing by preventing bleeding disorders
Me d icin e . 6th e d . Ph ila d e lp h ia , PA: Wo lte rs Klu w e r He a lth | that contribute to hematoma formation and subsequent
Lip p in co tt Willia m s & Wilkin s ; 2012:113.) infection.
(tex t continues on page 83)

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82 U N I T 1 Cell and Tissue Function

U N D E R S TA N D IN G W o u n d He a lin g
Wo u n d h e a lin g invo lve s th e re s to ra tio n o f th e in te g rity o f in ju re d tis s u e . Th e h e a lin g
o f s kin w o u n d s , w h ich a re co m m o n ly u s e d to illu s tra te th e g e n e ra l p rin cip le s o f
w o u n d h e a lin g , is g e n e ra lly d ivid e d in to th re e p h a s e s : (1) th e in a m m a to ry p h a s e ,
(2) th e p ro life ra tive p h a s e , a n d (3) th e w o u n d co n tra ctio n a n d re m o d e lin g p h a s e .
Ea ch o f th e s e p h a s e s is m e d ia te d th ro u g h cyto kin e s a n d g ro w th fa cto rs .

1 Fibrin
In a m m a t o r y Phas e. The
in ammatory phase begins at the
time of injury with the formation Epide rmis
of a blood clot and the migration of
phagocytic white blood cells into the
wound site. The rst cells to arrive,
the neutrophils, ingest and remove
bacteria and cellular debris. After De rmis
24 hours, the neutrophils are joined
by macrophages, which continue to
ingest cellular debris and play an Fa t
essential role in the production of
growth factors for the proliferative

Ne utrophil

Gra nula tion

2 tis s ue
P ro life r a t iv e P h a s e . The pri- Epithe lia l
ce lls
mary processes during this phase
focus on the building of new tissue
to ll the wound space. The key cell
during this phase is the broblast, a
connective tissue cell that synthesizes
and secretes the collagen, proteo-
glycans, and glycoproteins needed
for wound healing. Fibroblasts also
produce a family of growth factors Fibrobla s t
that induce angiogenesis (growth of
new blood vessels) and endothelial Blood ve s s e l
cell proliferation and migration. The
nal component of the proliferative
phase is epithelialization, during
which epithelial cells at the wound
edges proliferate to form a new
surface layer that is similar to that Ma cropha ge
which was destroyed by the injury.

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C H A P T E R 4 Cell Proliferation and Tissue Regeneration and Repair 83

3 contra ction
Wo u n d Co n t r a c t io n and
Re m o d e lin g P h a s e . This phase
begins approximately 3 weeks after
injury with the development of the
brous scar, and can continue for 6
months or longer, depending on the
extent of the wound. During this
phase, there is a decrease in vascu- Fibrous s ca r
larity and continued remodeling of
scar tissue by simultaneous synthesis
of collagen by broblasts and lysis
by collagenase enzymes. As a result
of these two processes, the architec- Blood ve s s e l
ture of the scar becomes reoriented
to increase its tensile strength, and
the scar shrinks so it is less visible.

(tex t continued from page 81)

The role of minerals in wound healing is less clearly can accomplish phagocytosis in a relatively anoxic
de ned. The major minerals, including sodium, potas- environment, they cannot digest bacteria. O xygen also
sium, calcium, and phosphorus, as well as trace min- contributes to signaling systems that support wound
erals such as copper and zinc, must be present for healing. Recent research suggests that almost all cells
normal cell function. Z inc is a cofactor in a variety in the wound environment are tted with specialized
of enzyme systems responsible for cell prolifera- enzymes to convert oxygen to reactive oxygen species
tion. In animal studies, zinc has been found to aid in (RO S). 24 These RO S function as cellular messengers
reepithelialization. that support wound healing, stimulating cytokine
action, angiogenesis, cell motility, and extracellular
matrix formation.
Blo o d Flow and Oxyge n De live ry
The availability of respired oxygen to wound tis-
Impaired healing due to poor blood ow and hypoxia sues depends on vascular supply, vasomotor tone, the
may occur as a result of wound conditions (e.g., swell- partial pressure of oxygen (PO 2 ) in arterial blood, and
ing) or preexisting health problems. 24,25 Arterial disease the diffusion distance for oxygen (see Chapter 21). The
and venous pathology are well-documented causes central area of a wound has the lower oxygen level,
of impaired wound healing. In situations of trauma, with dermal wounds ranging from a PO 2 of 0 to 10 mm
a decrease in blood volume may cause a reduction in H g centrally to 60 mm H g in the periphery, while the
blood ow to injured tissues. PO 2 of arterial blood is approximately 100 mm H g. 24
For healing to occur, wounds must have adequate Transcutaneous oxygen sensors are available for use
blood ow to supply the necessary nutrients and to in measuring wound oxygenation. From a therapeu-
remove the resulting waste, local toxins, bacteria, tic standpoint oxygen can be given systemically or
and other debris. M olecular oxygen is required for administered locally using a topical device. Although
collagen synthesis and killing of bacteria by phago- topical oxygen therapy is not likely to diffuse into the
cytic white blood cells. It has been shown that even deeper tissues, it does have the advantage of oxygen-
a temporary lack of oxygen can result in the forma- ating super cial areas of the wound not supported by
tion of less-stable collagen. 24 Wounds in ischemic tis- intact vasculature. H yperbaric oxygen therapy delivers
sue become infected more frequently than wounds 100% oxygen at two to three times the normal atmo-
in well-vascularized tissue. N eutrophils and macro- spheric pressure at sea level.26 The goal of hyperbaric
phages require oxygen for destruction of microorgan- oxygen therapy is to increase oxygen delivery to tissues
isms that have invaded the area. Although these cells by increasing the partial pressure of oxygen dissolved in

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84 U N I T 1 Cell and Tissue Function

the plasma. H yperbaric oxygen is currently reserved for contaminated at the time of injury. Although body
the treatment of problem wounds in which hypoxia and defenses can handle the invasion of microorganisms at
infection interfere with healing. the time of wounding, badly contaminated wounds can
overwhelm host defenses. Trauma and existing impair-
Im paire d In am m ato ry and Im m une ment of host defenses also can contribute to the devel-
Re s po ns e s opment of wound infections.
Approximation of the wound edges (i.e., suturing of
In ammatory and immune mechanisms function in an incision type of wound) greatly enhances healing and
wound healing. In ammation is essential to the rst phase prevents infection. Epithelialization of a wound with
of wound healing, and immune mechanisms prevent closely approximated edges occurs within 1 to 2 days.
infections that impair wound healing. Among the condi- Large, gaping wounds tend to heal more slowly because
tions that impair in ammation and immune function are it is often impossible to effect wound closure with this
disorders of phagocytic function, diabetes mellitus, and type of wound. M echanical factors such as increased
therapeutic administration of corticosteroid drugs. local pressure or torsion can cause wounds to pull apart,
Phagocytic disorders may be divided into extrinsic or dehisce.
and intrinsic defects. Extrinsic disorders are those that Foreign bodies tend to invite bacterial contami-
impair attraction of phagocytic cells to the wound site, nation and delay healing. Fragments of wood, steel,
prevent engulfment of bacteria and foreign agents by glass, and other compounds may have entered the
the phagocytic cells (i.e., opsonization), or cause sup- wound at the site of injury and can be dif cult to
pression of the total number of phagocytic cells (e.g., locate when the wound is treated. Sutures are also for-
immunosuppressive agents). Intrinsic phagocytic dis- eign bodies, and although needed for the closure of
orders are the result of enzymatic de ciencies in the surgical wounds, they are an impediment to healing.
metabolic pathway for destroying the ingested bac- This is why sutures are removed as soon as possible
teria by the phagocytic cell. The intrinsic phagocytic after surgery. Wound infections are of special concern
disorders include chronic granulomatous disease, an in persons with implantation of foreign bodies such
X-linked inherited disease in which there is a de ciency as orthopedic devices (e.g., pins, stabilization devices),
of myeloperoxidase and nicotinamide adenine dinucleo- cardiac pacemakers, and shunt catheters. These infec-
tide peroxidase (N ADPH )dependent oxidase enzyme. tions are dif cult to treat and may require removal of
De ciencies of these compounds prevent generation of the device.
hydrogen superoxide and hydrogen peroxide needed for
killing bacteria.
Wound healing is a problem in persons with dia-
betes mellitus, particularly those who have poorly Wo u n d He a lin g in t h e Eld e r ly
controlled blood glucose levels. 27 Studies have shown
delayed wound healing, poor collagen formation, and A number of structural and functional changes have
poor tensile strength in diabetic animals. O f particular been reported to occur in aging skin, including a
importance is the effect of hyperglycemia on phagocytic decrease in dermal thickness, a decline in collagen con-
function. N eutrophils, for example, have diminished tent, and a loss of elasticity. 29,30 The observed changes
chemotactic and phagocytic function, including engulf- in skin that occur with aging are complicated by the
ment and intracellular killing of bacteria, when exposed effects of sun exposure. Since the effects of sun expo-
to altered glucose levels. Small blood vessel disease is sure are cumulative, older persons show more changes
also common among persons with diabetes, impairing in skin structure.
the delivery of in ammatory cells, oxygen, and nutrients Wound healing is thought to be progressively
to the wound site. impaired with aging. The elderly have alterations
The therapeutic administration of corticosteroid in wound-healing phases including hemostasis and
drugs decreases the in ammatory process and may delay in ammation, cell proliferation, and resolution. 30
the healing process. These hormones decrease capillary Keratinocytes, broblasts, and vascular endothelial
permeability during the early stages of in ammation, cells display a reduced rate of proliferation. There is
impair the phagocytic property of the leukocytes, and also a reported decrease in angiogenesis and collagen
inhibit broblast proliferation and function. synthesis, impaired wound contraction, and slower
reepithelialization of open wounds. Although wound
Infe ctio n, Wo und S e paratio n, and healing may be delayed, most wounds heal, even in the
debilitated elderly patient undergoing major surgical
Fo re ig n Bo die s
Wound contamination, wound separation, and for- The elderly are more vulnerable to chronic wounds,
eign bodies delay wound healing. Infection impairs chie y pressure, diabetic, and ischemic ulcers, than
all dimensions of wound healing. 28 It prolongs the younger persons, and these wounds heal more slowly.
in ammatory phase, impairs the formation of granu- H owever, these wounds are more likely due to other dis-
lation tissue, and inhibits proliferation of broblasts orders such as immobility, diabetes mellitus, or vascular
and deposition of collagen bers. All wounds are disease, rather than aging.

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C H A P T E R 4 Cell Proliferation and Tissue Regeneration and Repair 85

1. Sephel GC, Davidson JM . Repair, regeneration, and brosis. In:
Rubin R, Strayer DS, eds. R ubins Pathology: Clinicopathologic
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ce ll typ e , o r w h e n re g e n e ra tio n ca n n o t re s to re th e Wolters Kluwer H ealth/Lippincott Williams & Wilkins;
in ju re d tis s u e , b y re p la ce m e n t w ith b ro u s (s ca r) 2012:83113.
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a n d re m o d e lin g . In w o u n d s h e a lin g b y p rim a ry
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