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■ Introduction

■ Pathology- the work of pathologist/physicians whose focus is on the physical


changes present in diseased organs and tissues.
■ Pathophysiology- the abnormal functioning of diseased organs with application
to patient care. (physiology gone bad)
■ Etiology- the study of the cause of a disease
■ Idiopathic- etiology is unknown
■ Three kinds of etiology:
1. Genetic etiology
○ Genes are responsible for some structural or functional defects.
2. Congenital etiology
○ Environmental issues effect prenatal development
○ Ex. Cystic fibrosis
3. Acquired disease
○ Encountered later in life, developed over time
○ Tuberculosis, emphysema, hepatitis

■ Symptoms- reflect the patients subjective experiences, what the doc looks at
■ Signs- are detected by the patient, rash or increased body temp
■ Syndrome- combination of signs and symptoms
■ Sequala- a condition resulting from a disease
■ Acute- short, rapid growth
■ Chronic- long duration
■ Insidious- minor changes that don’t arouse immediate concern
■ Local- one region of the body
■ Focal- limited to one or more distinct sites
■ Diffuse- is uniformly distributed

■ Diagnosis- the identification of the patients specific disease
■ Prognosis- the prediction of a particular disease’s outcome


Chapter 1

■ At the subcellular level organelles perform various tasks for the overall function

■ The specialized functions are because of the chemical level. Atoms and
molecules have random patterns of organization. Cells counter this, showing the
distinctive difference of living vs non-living.

The Plasma Membrane

■ Cell/plasma membrane is made up of phospholipid, cholesterol, glycolipid,


protein, and glycoprotein.
1. It defines the size and shape of cells and acts as a container.
2. Selectively permeable – able to pass molecules between cells and environment;
like water. The movement of nutrients and waste. This is done through active
transport expending energy.
○ Transporting ions through ion pumps
○ Endocytosis- inward movement
○ Exocytosis- outward movement
3. Provides the surface were the cell interacts with its environment. This can affect
the permeability or cellular metabolism. Due to receptors forming carbohydrate
component of glycoprotein.

The Mitochondrion

■ Many molecules that enter the cell through its membrane serve as an energy
source. Glucose is the main energy source. The mitochondria extracts it
converting it into ATP, available for transfer to various other metabolic
pathways. Produced during the Krebs cycle, chemical transformations producing
CO2.
■ Requires oxygen (aerobic). The sites of energy metabolism lines their enzymes.
The enzymes are organized in the crista, folds, organelles are rich in protein,
enzymes, much cell activity is devoted to protein synthesis.

Granular Endoplasmic Reticulum

Protein synthesis occurs in the cytoplasm (the fluid of the cell, water, solutes, and
organelles)
○ Endoplasmic reticulum (ER) – connected by cisternae with small masses
called ribosomes (protein) stores with the GER

The Golgi Complex

■ Consists of stacks of cisternae, which store the proteins often with carbohydrate
or lipid to form a fully functional product for secretion. To be able to secrete it is
passed to vesicles (sacs) to be transported to the cell membrane
Agranular Endoplasmic Reticulum

1. it detoxifies, to chemically degrade hormones, drugs, or toxins


2. For a formation of lipids, phospholipids, triglycerides, and steroids

The Lysosome

■ Digest enzymes that are not needed. Also known as a phagosome

The Cytoskeleton

■ Thin filaments that support and organize of organelles/cell structure

The Nucleus

■ The control of the cell. Contains chromosomes/DNA structure

Causes of cell injury

■ Three ways a cell can be injured:


○ The lack of a substance necessary to the cell – a defiency
○ The presence of a substance that interferes with cell function – poison or
intoxication
○ The loss of the cell’s structural integrity – physical injury, trauma

Deficiency

■ Cells need a constant supply of chemical nutrients and energy. Heart attacks are
of the most common because there is a lack of oxygen or nutrients. Lack of
thiamin causes damage to nervous tissue.
■ Primary- there are none present
■ Secondary- they are there, but cannot be absorbed
○ Genetics can cause precursors
○ Viral action- infected, having a heavy demand for particles disrupting the
cell’s metabolism

Intoxication

■ Exogenous Toxins- are external, biological, or nonbiological


○ Biological- are known as infections
○ Nonbiological- chemicals outside the body either inhaled or swallowed

■ Endogenous Toxins- within the body
○ Genetic- which causes toxin to be produced
○ Impaired Circulation- when metabolic by-products accumulate. The injury
occurs by binding to the cell structure, disrupting function

Trauma

■ Trauma is a physical injury. The integrity of the cell can be completely lost.
○ Extreme cold (hypothermia) disrupting cell proteins
○ Excessive heat- denatures cells, disforming helix
○ Burns, suns radiation can be gradual
■ Ionizing radiation- through x-rays/nuclear radioactivity. Produces free radicals.
○ Strips electrons from cell molecules
○ Mechanical pressure, tumor or expanding arteries
■ Physical injury- bacteria from potent enzymes/viral infections
■ Immune system- when attempting to protect us it could end up hurting us.
Antigen- antibody at cell surfaces cause disruption on cell membrane. One virus
can produce several other occurring viruses.
■ These viruses cause other cells to attack this now foreign cell which causes cell
death/trauma
Cell Injury: Responses and Effects
● Cells can activate various adaptive responses that can them cope with certain
situations
● A cells damage is determined by the nature, intensity, duration, and number
of exposures to it
● When a cell is restored from injury this is known as a reversible change.
Reversible Changes: Functional
● Cells are very adaptive when necessary and once back to normal can then be
deactivated.
● Alternative Metabolism- in unfavorable conditions, a cell can employ
alternative metabolic pathways that allow it to adjust to the conditions
○ This can be seen when oxygen dependent (aerobic) is threatened, so
tissues adapt to glycolysis, allowing ATP to be reproduced
anaerobically
○ Also when glucose can not be used as an energy source, many cells
turn to fat or protein as a fuel. This is until glucose levels return to
normal
● Altered Size- when size changes are adaptively capable
○ hypertrophy- cell and organ enlargement that occurs in response to
increased demands
■ Myocardial cells increase in size/strength to pump through a
narrow heart valve
○ hyperplasia- new cells are formed by mitosis to respond to increased
demand
○ Atrophy- shrinking
■ most common when there is a reduced workload
■ starts by gradually shutting down their specialized functions, is
done by degrading them with lysosomal enzymes in
aautophagosomes
■ Apoptosis- a reduction in cell numbers by a process of self-
destruction
■ process is genetically regulated
■ surrounding cells slowly move into fill in the previous cells space
■ commonly done when overdeveloping cells are produced for a
fetus or unneeded immune cells
○ Cell Stress Proteins- happen when a shock or internal stress occurs
■ The proteins unfold and clump together to accumulate in the
cytoplasm
■ The cells that are infected start to denature, to stabilize
denaturing proteins to be expelled before they can form a clump
while the normal try to clump quickly
○ Organelle changes- by altering its complement of organelles
■ The liver has enzymes that help degrade toxic chemicals
■ This production occurs only when a toxin persist to continue to
show up
Cell and Tissue Accumulations
● many injuries can directly or indirectly disrupt capability, as a result
substances accumulate within the cell; like water
● Hydropic Change- occurs when cellular energy production is decreased, which
causes the ions pumps fail to eject (Na++)
○ an increase of osmotic pressure
● Fatty Change- Fat accumulates within the cell
○ cellular fat increases slowly until nucleus are pushed to the periphery
of the cell
○ may rupture the cell which will cause surrounding damage
■ happens often in kidney, liver, and heart
● Residual Bodies- the cell’s capacity to cope with potentially threatening
bacteria or to deal with damaged organelles
○ They are derived from phagosomes, but retain when lysosomes are
inadequate to to complete digestion
○ lipofuscin granule- containing undigested cell membrane lipids
■ Found in neurons, liver, and myocardium
○ More and more bodies accumulate with age
● Hyaline Change- a material that deposits protein and is found in damaged
arterioles, renal tubules, damaged liver cells, and neurons.
○ Pathogenesis of protein accumulation is present in the tissue with
hyaline
Reversible Changes: Structural
● depends on the nature and duration of the injury
● the plasma membrane is quick to show effects
○ become stretched and distorted producing cytoplasmic bulges called
blebs
○ could exhibit focal coiling that resemble whorled pattern relating to
myelin called myelin figures
● when cellular swelling occurs changes can be seen in the golgi complex, ER,
and mitochondria
○ Ribosomes can be seen floating within an injured cell
Irreversible Injury and Necrosis
● are more damaged than reversible cells
○ extreme distortions
○ rapid inflow of sodium, calcium and water
○ gaps allow vital cell constituents to escape
○ fewer lysosomes
○ The largest indicator of irreversible cell injury is an altered nucleus
■ Karyolysis- nuclear DNA is degraded; fades and melts into the
cytoplasm
■ Pyknosis- nucleus may shrink or condense
■ Karyorrhexis- nucleus breaks up into dense fragments that
disperse in the cytoplasm
Mechanisms of Irreversible Injury
● damage to the cell membranes, effect permeability and cytoplasm
organization
○ severe swelling from sodium influx
○ large flow of calcium into the cell
■ High calcium causes protein denaturation; losing enzyme
function
■ This particular effects the function of the mitochondria
○ A damaged cytoskelton could cause the cell to rupture
Cell Death
● A cell can make a full recover and adapt
● Cell recovers, but not normal functions
● Cell death
○ at has reached ‘the point of no return’
● Necrosis- the condition of cell death
○ Substantial changes occur-
■ cell broken down by endogenous enzymes and phagocytic cells
○ Lysosomes initiate chemical breakdown of cell
● Coagulation necrosis- tissues become firm
○ cell proteins quickly denatured by high levels of acid and calcium
○ Lysosomal enzymes are unable to digest until phagocytic blood cells
arrive to finish breakdown
● Caseous necrosis- has a pale, granular, cheese like appearance
● Gangrene/ gangrenous necrosis- happen when access is gained to an area of
damage caused by reduced blood flow (ischemia)
○ Putrefaction- foul-smelling gases produced
○ wet gangrene- liquefaction
○ dry gangrene- coagulation is sustainde
● Liquefaction necrosis- coagulation does not occur, necrotic tissue breaks
down quite promptly
● calcification- persistent injury or slow developing
● dystrophic calcification- calcium crystal progressively produce large masses
leading to brittleness and affected tissue
● Metastatic Calcification
○ it occurs in otherwise normal, as opposed to necrotic tissue
○ the deposition is a consequence of an excessive systemic calcium
level, or hypercalcemia
■ found mainly in lung, kidney blood vessels, or stomach
membrane
Tissue Vulnerability
● Ischemia- cns neurons are highly sensitive bc of high metabolic rate and
depend on glucose as their energy source
○ underlying cause of a stroke
○ while the kidney, liver and fibroblast are tolerant of this
● Intoxication- Carbon tetrachloride, is inhaled and transported to the liver
○ does not affect respiratory tract, but once in the tissue it produces a a
toxic free radical
● Ionizing Radition- Actively dividing cells undergoing DNA replication are
injured mostly; skin
● Viral Infection- enter and then disrupt the cells from within
○ A virus attacks specific cells

Chapter 2 – Inflammation

○ All conditions that end in “itis” are inflammatory conditions


○ Examples being: dermatitis, meningitis, pericarditis
○ Inflammation is a complexly orchestrated response to injury that serves to
destroy the source of injury, remover the accumulated debris, and trigger the
repair process.

Normal Vascularized Connective Tissue


○ This tissue is known as loose or areolar connective tissue.
○ Located in the dermis of the skin, mucosa lining of the G.I. and urinary tract,
epithelium of respiratory tree, muscle fibers, and lining of joint capsules.
○ Relaxation of precapillary sphincters permits blood flow through portions of the
capillary bed. Metarterioles can shunt blood past the tissue when the precapillary
sphincters, which regulate blood flow through the tissue, are closed. (figure 2.1)
○ Endothelial junction- two adjacent endothelial cells meet, their edges overlap and
a thin layer of glycoprotein fills the gap. Mostly found in loose connective tissue.
Inflammation will loosen these junctions.

○ Blood hydrostatic pressure (BHP)- pressure of blood enclosed within vessels

○ Tissue hydrostatic pressure (THP)- pressure of fluid within the tissue


○ Fluid is exchanged back and fourth based upon the blood osmotic pressure
(BOP) and the tissue osmotic pressure (TOP). For example, under arteriolar
dilation, BHP predominates, forcing more fluid through the capillary.

Acute Inflammation
○ An increased flow without increased permeability, such as an active muscle,
moves more fluid to the tissues, but this fluid simply represents an increase in
volume and not a change in the nature of the fluid. Such a fluid is called a
transudate. It has relatively little protein. The opposite is called exudate, which
forms with increased permeability at the capillary is rich in proteins and cells,
which drastically reduces BOP and increases TOP.

○ Why is the accumulation of fluid and plasma proteins important at site of an


injury?

1. Dilution of toxins
a.Preventing any further damage substances might do
2. Increased pain, caused by swelling
a.The pain forces limited use, helping to prevent more damage
3. Presence of antibodies
a.Without the body changing vascularity and permeability these antibodies would
stay in the blood; however, they don’t and they help with disease
fighting.
4. Proteins
a.Help amplify the injury response, kills organisms and promotes phagocytosis of
organisms causing tissue damage.

Descriptive Classification
○ Acute inflammation can be classified by the nature of their fluid exudates. The
more serious the injury the more fluid and proteins leave the blood
○ Serous inflammation- response to mild injury, where only fluid is allowed to
escape to the intercellular spaces. Endothelial cells contract only slightly leaving
protein in the blood. A good example is the watery fluid seen in the blister of a
burn
○ Suppurative inflammation- more severe injury causing greater necrosis. Here
neutrophils form the thick, white-green fluid called pus.
■ Cellulitis
• Diffused (spread) inflammation of pus
■ Abscess
• Localized accumulation of pus
■ Cyst
• A fluid filled sac usually left over from inflammation
○ Hemorrhagic inflammation-Large number of red blood cells (erythrocytes)
escaped due to capillary damage.
The Formation of Exudate: Cellular Factors
○ Leukocyte emigration- the outpouring of large numbers of white blood cells from
the blood. Inflammation greatly increases the emigration of leukocytes, due to the
changes in blood flow.
Margination
● axial flow- blood flowing at normal rates
○ bloods (erythrocytes, leukocytes, platelets) move in a central column
○ plasma is on the periphery flowing smoothly along endothelial lining of
the vessel
● In inflammation fluid is lost and flow rate decreases, the central column of
elements enlarge and the leukocytes now lie along the periphery known as
margination
Rolling, Pavementing, and Adhesion
● The leukocytes now in the periphery adhere to the endothelial surface, where
they flatten
○ This is important because this causes the stat of motion of leukocytes
to discontinue so it can transition to the inflamed area easier
Transmigration
● The leukocytes move to an endothelial junction, this is where it squeezes
past the endothelium, continuing through the cells basement membrane.
○ occurs at the endothelial gaps of post-capillary venules
● diapedesis- process of emigration, the passive movement of red cells that
may occur at the same site
● Two types of leukocytes
○ neutrophils- the earliest, described as polymorphonuclear cells (PMNs)
multi nucleated
■ last only up to 48 hours then undergo apoptosis
○ Mononuclear cells or monocytes- large and when in the tissue spaces
they are called macrophages
■ longer lasting
Phagocytosis
● A phagocyte must be activated and move to the problem, to attach to it.
○ It engulfs/destroys the target by releasing enzymes and toxins stored
in its lysosomes.
Chemotaxis
● When a phagocyte is in an inflamed tissue and encounters an increased
chemical attraction, this is chemotaxis.
○ exogenous chemoattractants are both peptides and lipids.
● This occurs when the presence of specific receptors bind and trigger
biochemical events, making a larger and more active phagocyte
○ Directing movements is done by rapid assembly of actin molecules
Recognition and Attachment
● Opsinization- greatly enhances phagocytosis
○ opsonins are substances from the plasma that have an affinty for the
surface features of foreign particles
■ leukocytes are able to respond because they contain opsonins
binding sites
● once bond it is readily engulfed
Engulfment and Destruction
● A phagocyte encloses around the particle while the granular-appeared
lysosomes destroy it
○ once merged together lysosome numbers reduce and is said to be
degranulated
● If the particle is too big (multi-cellular) it may be regurgitated into the tissue
spaces
○ can happen to immune complexes exposed on the basement
membrane
■ A leukocyte attempting to engulf this experiences ‘frustrated
phagocytosis’
■ Releasing toxic and degraditive substances that damage the
basement membrane and surrounding cells/matrix.
● extensive tissue damage can occur
● oxygen-independent- mechanisms involve the release of performed
substances that damage bacterial cell walls, disrupt bacterial replication, and
produce a low pH, which may be directly toxic and may indirectly aid the
function of other enzymes.
○ Restriction of bacterial mitosis by iron-binding loctoferrin
○ Bacterial cell wall damage by:
■ BPI- permeability
■ lysozyme-coat-digesting
■ major basic protein- toxic to parasites
● Oxygen-dependent- more important than oxygen-independent, accomplished
by the creation and release of oxygen free radicals: ‘singlet-oxygen’
○ Halogenatin is the most potent bactericidal agent produced by
neutrophils
■ focuses on the destruction of engulfed organisms
● In regruiated or frustrated phagocytosis, the destruction is turned on the
host tissues (bystander injury)
Bacterial Defenses
● Some bacteria have evolved a variety of defenses against phagocytosis
○ exotoxins killing leukocytes or inhibit chemotaxis
○ slimy coat, which opsonins have a difficult time binding to
○ touch capsules
○ shedding substances that bind opsonins
○ producing cytotoxins that protect against enfulfment
Defects in Leukocyte Function
● In the chain of events at any point will impair host defenses, causing a defect
○ Leukocyte defects are often chronic, involving bacteria with low
infection potential
■ Chronic granulomatous, disease of childhood-genetic defect in
phagocyte killing due to impaired production of oxygen free
radicals
■ Chediak-Higashi syndrme, defects in bot phagocyte motility and
degranulaton, often leading to early death
■ Diabetics- defects are caused by circulatory problems,
preventing inflammatory cells to be delivered to the
inflammation site
■ Drugs (steroids, morphine, tetracycline, and chloamphenicol)
Chemical Mediation of Inflammation
● Injury initially causes certain chemical substances to be produced or release
at injury site to cause acute inflammation
● Initiators- trigger the same vascular or cellular responses of inflammation
events (nonspecific)
○ signal a risk of cellular injury
● Chemical mediators- indirectly achieved from initiators
○ may have multiple responses but ultimately achieve an inflammatory
response
○ works in a positive feedback loop
■ tend to be short lived signals
■ A single occurrence (bee sting) can be resolved quickly
● But several (bee stings) can cause an allergenic reaction
(anaphylactic shock)
● Can be a long term issue which triggers low levels, but
severe damage can occur
Cell-Derived Mediators
● Histamine- familiar to allergy suffers, decreases vascular permeability
○ antihistamines reverse this process by inducing venule endothelial cell
contraction (allows exudate to form)
■ Histamine is released from mast cells and platelets
● Mast cells are leukocytes that have a specialized
location/function. Lie along the skin, GI tract mucosa, an
respiratory tree
○ They are the first line of defense against many
pathogens
● What triggers degranulation? (the release of mediators from preformed
granules)
○ Cold, heat, trauma, and encounters with foreign antigen
■ Dealing with parasites and worms
■ Downside they are triggered by allergens which produce
immediate symptoms
● swelling and mucous secretion
○ To be effective antihistamines has to be taken prior to exposure of
allergen
● Serotonin- released from platelets after encountering collagen in the
basement membrane
○ same effect as histamine
● Eicosanoids- products of the metabolic transformation of the membrane
phospholipid-derivative arachidonic acid (AA)
○ Slow compared to histamine and serotonin
■ All leukocytes and mast cells produce AA
■ AA passes through either of two enzyme-mediated pathways
● Lipoxygenase-route producing leukotrienes
○ Leukotrines take up the role of increasi vascular
permeability left of from histamine and serotonin
○ some produce vasoconstriction
○ trigger leukocyte adhesin and chemotaxis
● Cyclooxygenase- route producing prostaglandins and
thromboxans
○ prostaglandins- produce vasodilation and
enhancing the effect of other mediators
■ There are two ways that chemicals can interrupt the production
of eicosanoids
● Corticosteriods- shut off the supply of AA
○ counted on to shut down an inflammation if it gets
out of control (like in asthma)
● Nonselective cyclooxygenase (COX) inhibitors- inactivate
only the pathway that leads to the productions of
prostaglandins and thromboxanes
○ Acetylsalicylie acid (ASA), acetaminophen, and
NSAIDS are COX inhibitors
○ COX-1-the covering mucus for the GI tract and
responsive rfusion of the kidneys
○ COX-2- inflammatory response, pain, and fever
■ Nitric Oxide (NO)- an important signal in the nervous system,
the vasculature, and inflammatory response
● Vasculature- potent vasodilator
● nervous system- a neurotransmitter-like role and
participates in the targeted management of local
perfusion
● Inflammaotry response- is activated macrophages and
perform many functions
○ makes it harder foeukocytes t roll and attach,
reducing the release of histamines/serotonin
○ It has a favorable antibacterial effect
■ if too much person can go into shock
■ Platelet-activatin factor (PAF)- released by basophils and mast
clees, macrophages, neutrophils,platelets and endothelial cells;
causes platelets to aggregate and degrnulates
● but also modulates vascular tone and facilitates other
inflammatory processes
Plasma-Derived Mediators
● Cascade- formed at the end of a sequence of activation steps
○ a postive feedback system
○ a number of inactive proteins circulate in the plasma
■ an initial activation event occurs to activate a protein, then a
second, third..etc
○ four interrelated cascades can be triggered by a protein known as
Hagmen factor (Clotting factor XII):
■ blood coagulation and fibrinolytic cascades function in
inflammation and blood loss prevention
■ kinin-restricts its role to mediating inflammation
● bradykinin- contributes to the pain of inflammation
○ tension and pressure from damaged site
○ lowered pH and potassium from damaged cells
■ complemet-linked to inflammation and the immune system
● consists of 20 circulating proteins
● Sequential activation produces a complex of five protien
caled the membrane attack complex (MAC)
○ Destroys invading microorganisms by punching
holes in their membranes
○ anaphylatoxins-act as mediators of inflammation,
dilation, permeability, chemotaxis, phagocytosis,
an histame release from mast cells
■ triggered by microorganisms surface and
antibody conjuntion in defensive role of the
immune system
● are done in rapid dramatic fashion
○ drops suddenly ending the acute inflammation
■ mediator is exhausted or terminated
■ cascades are triggered that reverse the
mediating cascade
■ anti-inflammatory
■ antioxidant
■ antiproteolytic agents to former injury site
○ The result quenhes acute inflammation, analogous
to the process that limit coagulation of blood
■ sets stage for healing process
■ Antibody- plasma-derived mediator that is not formed by a
cascade
● a key immune system element that may be an initiator
that activates the complement cascade
Systemic Effects of Acute Inflammation

· Familiar effects of systemic inflammation include: fever, loss of appetite, very


deep sleep, rapid weight loss, residual weakness.
· Lymphadenitis- swollen lymph nodes
· Lymphangitis- a bacterial infection at lymph nodes
Temperature
· Application of cold to swelling causes vasoconstriction to prevent heat loss,
the reduced blood flow has the effect of reducing formation of fluid exudate and
swelling is relieved. Application for more than ten minutes will trigger the mast
cells to degranulate therefore worsening the inflammation. Applying cold will help
build up phagocytes and then applying heat will active phagocytosis.
Elevation & Pressure
· Fluid exudate and swelling can be reduced because blood flow is slowed down
to gravity. Same for pressure, pressure can prevent exudate from forming by
increasing the pressure in the tissues, so the fluid is prevent from leaving the blood
vessels.
Drug Therapy
· Antihistamines- drugs that block the action of histamine at its blood vessel
receptors.
· By blocking cyclooxygenase activity, agents like ibuprofen and aspirin block
prostaglandin synthesis and removes an important inflammatory mediator.

Chronic Inflammation
· Chronic inflammation is considered to be after six weeks duration
· Over time fluid exudate diminishes and cellular response assumes dominance.
· In this case the attack of an agent and the attack of our defense are equally
strong and never able to overwhelm one another.

Chapter 3: Fever
I. What is fever?
A. Elevation of the body temperature above its normal range
B. Also known as pyrexia
C. Associated with disease and infection
D. Fever represents an upward adjustment of the temperature level that the system seeks to
establish and maintain
II. Normal Thermoregulation
A. Normal oral temperature=36.7oC
B. Temperatures normally don’t vary more than ±0.5 oC
C. Rectal temperature is the most accurate form
1. Core temperature gives you a more true reading
2. Oral temperature is affected by ingestion of cold or hot substances or by breathing patterns
D. Temperature is closely regulated because temperature changes can affect cellular
functions
1. Warm-blooded animals and heat conservation
2. A fever of 43 oC results in death within hours
E. Maintaining a normal temperature is possible by balancing heat production against heat
loss
1. Heat production: energy is constantly produced and released from living tissues in the form
of heat
a. At rest, the liver and heart are the source of most body heat
2. Heat loss: achieved through heat delivery to the body surface
III. Mechanisms of Heat Production
A. Shivering—a patterns of rapidly alternating skeletal muscle contractions that produce no
skeletal motion
B. Non-shivering Thermogenesis
1. Thyroid hormone: tells muscles to stimulate metabolism and generate heat
2. Brown adipose tissue: fat that is not intended to store lipids, but to break down triglycerides
through the Kreb’s Cycle
a. Produces only heat, no ATP
b. Present in babies and hibernating animals to keep body temperature at within normal
ranges
3. Vasoconstriction and vasodilation
IV. Mechanisms of Heat Loss
A. Radiation—heat energy moves direction away from the warm skin surface
1. Example: feeling the heat of a stove top without touching it
B. Evaporation—water at the skin surface is converted from liquid to gas
1. The process consumes heat from the surrounding skin
2. Accounts for 30% of heat loss at rest
C. Conduction—direct transfer of heat by physical contact between the body and a cooler
surrounding medium
1. Accounts for up to 70% of heat loss from the skin
D. Convection—heat is carried away by movement of the air or water surrounding the body
1. Example: immersion in water
V. Regulation of Heat Loss
A. Types of Regulation
1. Reflex shivering
2. Thyroid hormone (TH)
3. Behavioral Responses
4. Changing body position, adding layers or blankets
B. Skin regulation
1. Dermal blood flow
a. When blood is moved near the surface, more heat is lost
b. When blood is moved farther from the surface, less heat is lost
2. Sweat production
a. Changes in sweat production cause greater or less heat loss
b. Insensible water/heat loss: loss of heat by evaporation form the skin and lungs
C. Negative Feedback Control of Body Temperature
1. The temperature control system has one or more effectors
a. Effectors= components that can respond to bring about changes in temperature
o Major Effectors: dermal arterioles, sweat glands, skeletal muscle
2. Temperature Integration Center (TIC) decides how to regulate temperature based on
information sent through the anterior hypothalamus
a. Information is sent via sensors (types of thermoreceptors) which are sensitive to
temperature changes
b. The system maintains the particular variable close to a certain value (set point)
3. Loss of homeostatic control
a. Wet clothing, intoxication (impaired judgment and neural function), competitive exertion,
abnormally low body fat, dehydration, illness
b. If it’s too hot, what mechanisms are used?
o Vasodilation
o Sweat production
*parts of a negative feedback loop
D. Failure of Normal Thermoregulation
1. Hyperthermia (when you’re too hot!)
a. “Loss of homeostatic control resulting in rising core temperature”
b. Increases metabolic rate of tissues (more heat is produced)
c. Classic heatstroke: occurs in hot, dry environments when body temperature exceeds 105
oF
o Signs: hot, dry skin
o This causes: delirium, seizures, tachycardia (increased heart rate; ≥120 BPM when at
rest), dehydration, anhydrosis (no sweating)
o The thermoregulatory system has shut down
o You are now pumping hot blood up to the brain, which induces delirium and seizures
d. Exertional heatstroke: occurs in athletes whose intense activity in a hot environment
generates heat faster than it can be cleared
e. Malignant hyperthermia of anesthesia: when a genetically predisposed person is given
certain anesthesia/muscle relaxants, then develops muscle rigidity and severe hyperthermia
f. Heat exhaustion: a milder form of hyperthermia
2. Hypothermia (when you’re too cold!)
a. “Prolonged or extreme exposure to cold”
b. Mild hypothermia: the core temperature is 90-95 oF
o This causes: intense shivering and muscle cramping, which may impair self-rescue efforts
c. Severe hypothermia: the core temperature is <90 oF
o This causes: shivering stops (it is no longer effective, pulse and respiratory rate slow (to
avoid heat loss), BP drops, impaired judgment, altered consciousness, and a sense of euphoria
*highly maladaptive behaviors
o “After drop”= continuing drop in core temperature after salvage mechanism begin
§ Muscle activity is returning cold blood to the body core
d. Heat loss is 30x faster in water than in air via convection
VI. Fever
A. Fever is most commonly a prominent manifestation of inflammation
1. “Febrile”=a feverish patient
2. It is part of a broad, integrated acute phase reaction
a. The hypothalamus orchestrates endocrine responses
o Release of glucocorticoids (stress response)
o Decrease in vasopressin (Anti-diuretic hormone)
o Increased HR and BP
o Blood is directed towards the body core
o Higher-order behaviors are triggered
§ Chills, which prompt warmth seeking, appetite loss, and malaise
3. Elevated temperature DOES NOT suggest a defect in the temperature-regulating control
system
o The system is functioning properly, but a new set point has been generated by the TIC
o This causes: pallor (from vasoconstriction in skin) and chills (from vasodilation in body
core to redirect blood flow)
4. A pyrogen is a fever-causing substance
a. Endogenous pyrogens (EP) cause the set point to be raised
o Caused by interleukins from macrophages and monocytes
§ Mononuclear phagocyte group
o Can directly bind to the vagus nerve, which innervates all inner organs (“gizzards and
innards”) and sends a signal to the anterior hypothalamus
b. Exogenous pyrogens are from bacterial endotoxins
o They may not directly act as a pyrogen, but the toxic secretions have the same effect as
EPs
B. The Role of Fever
1. Positive Aspects
a. Some viruses and infectious agents are temperature-sensitive, so the spike in temperature
may kill/denature the agent
o This is an adaptive response, as long as the temperature is below 105 oF
b. Fever causes enhanced immune performance
o Leukocytes and antibodies are more effective
o Phagocytosis is more efficient
2. Negative Aspects
a. Fevers greater than 105 oF can compromise cardiac function
o The fever increases cardiac workload (increased HR and neural oxygen uptake)
o Warmer tissues increase metabolic rate, thereby producing more heat
o Risk of brain damage
o Head injury can cause the hypothalamus to not work properly, sending fever levels up past
the 105 oF max for safety
3. Fever of Unknown Origin
a. Fever of at least 38.3 oC (101 oF) continues for at least 3 weeks without a cause
b. Causes:
o Infection (31%)
o Malignant tumor (21%)
o Collagen-vascular disease/autoimmunity (14%)
o Other (22%)
4. Drugs and Fever (Antipyretic Therapy)
a. The most common drugs used to reduce fever are Aspirin and acetaminophen (Tylenol)
o Both block prostaglandin production
§ Decreases the set point back to normal
§ Activates heat loss mechanisms
**Cool the brain, then the body**

Chapter 4: Healing
I. Healing: the restoration of structure, strength, and sometimes function
A. Example: scarring
B. Inflammation bridges from injury to healing
1.Benefit: this prevents further damage, cleans out infection and debris
II. Components of the Healing Process
A. The healing process provides for the replacement of lost tissue through the proliferation of
adjacent undamaged tissue
B. Most organs are formed of parenchyma cells
1.Parenchyma: cells that are bound together and supported by connective tissue and blood
vessels that combine to form the stroma
C. Regeneration
1.Regeneration occurs when tissue is replaced from parenchyma
2.Cells lost through injury may be replaced by mitosis of the adjacent parenchyma
a. Regeneration offers the ideal response to tissue loss because the new tissue assumes
normal functions
3.Not all cells have the same regenerative capacity
a. Labile cells: must divide continuously to replace cells that are constantly being depleted by
normal processes
1) Examples: epithelia of the skin, mucous membranes, duct linings, red bone marrow
2) Regeneration involved accelerating the normal mitotic rate
b. Stabile cells: the cells slowly divide after adolescence
1) The cells are able to function normally throughout life (high mitotic rates are not required)
2) Examples: glands, the liver, osteoblasts, smooth muscle fibers, vascular endothelium
3) Regeneration involved increasing the mitotic rate, forming an organized pattern dictated by
the remaining undamaged stroma
§ When the stroma is disrupted, there is a disorderly regeneration process, which leads to
functional deficiency
c. Permanent cells: lose all mitotic ability soon after birth, never to be regained
1) This results in functional loss if tissue is damaged
2) Examples: nervous tissues, cardiac and skeletal muscle
3) Cells are replaced by scar tissue
D. Repair
1.Repair occurs when fibrous CT is laid down to restore the strength and structural integrity of
damaged tissues that cannot regenerate
a. Fibrosis=scar formation from collagen-rich replacement tissue
2.Collagen formation
a. Fibroblasts form the fibers
1) They are resistant to damage and are likely to survive at the injury site
b. Procollagen is secreted; outside of the cell, these fibers are enzymatically altered to that they
link together to form long filaments
c. These long filaments join together to form thicker collagen fibers, which join to form collagen
fiber bundles
d. Cells have great tensile strength
1) Cross-linking allow the fibers to resist being pulled apart
2) The bundles realign along the injury site to provide the greatest strength
3.Scarring
a. The process begins in the ECM, which contains elastic fibers and glycoproteins
1) The glycoproteins contain a small number of sugar unites
b. Proteoglycans have a dominant carbohydrate component (aka mucopolysaccharides)
c. The ECM directly contributes to the formation of a strong and well-anchored scar
1) When damage occurs, blood floods the area and plasma fibrinogen is converted to fibrin
§ Fibrin forms a mesh that entraps blood cells and tissue debris (clots)
2) Organization=the elimination of the clot by phagocytosis and its replacement by scar tissue
3) Water follows, hydrating the tissues
E. Revascularization (Angiogenesis)
1. Revascularization is the production of new blood vessels to supply and drain the damage site
a. This occurs in the loose exudate during regeneration and repair
b. Granulation tissue: new capillaries grow into the exudate
1) The exudate takes on a pink and granular appearance
2) The tissue is a transition material for fibrosis
c. Endothelial buds form on capillaries, growing out until they reach another bud and fuse into a
new capillary
1) Cells in the bud vaculolate to form lumen (This is called canalization)
2) The new capillaries are leaky and highly permeable, which accounts for continued swelling
seen after an injury
F. Surface Restoration
1.Surface restoration is the regeneration of the protective epithelium that covers the body and
organ surfaces
a. This occurs because epithelial cells are labile
1) There is a zone of active mitosis near the wound edge
b. Abrasion=a scraping injury of the skin, where only the epidermis is lost
1) Sliding of epithelial cells occurs at the surface of the underlying dermis (Epithelial migration)
§ The cells secrete new basement membranes
§ Damaged hair follicles and skin glands cannot regenerate to form functional replacements
because they are stabile
III. Wound Healing
A. Primary Healing (Healing by First Intention)
1.Healing of an incision or small cut/abrasion
a. Damage is minimal and the wound edges are close to each other
2.Clotting serves to limit further blood loss and to seal the wound from dehydration and infective
microorganism infestation
a. The surface of the clot dries up, forming a scab
b. Phagocytes quickly work to clean the wound, loosen and digest the clot
1) Hemoglobin released from entrapped red cells is broken down to yield pigments that
contribute to the early discoloration sometimes seen at the wound site
3.As surface restoration proceeds, pigment-producing melanocytes cannot regenerate and so
they are not replaced (this is why scars are not the same color as the surrounding skin)
4.Strength of fully healed skin never reaches preinjury levels
a. Maximum strength is 70-80% of normal
B. Secondary Healing (Healing by Second Intention)
1.Healing of a wound whose edges are not closely apposed
a. These wounds produce more debris and take longer to heal
2.The same steps are taken as in Primary Healing, but with two added factors
a. There is a larger amount of granulation tissue needed to fill the wound gap
b. Wound contraction=the wound edges draw towards the center
1) Reduces size of the gap that the granulation tissue must fill
2) Reduces the area that the new epithelium most restore
3) Contraction depends on myofibroblast cells that exhibit contractile capability while
resembling a fibroblast
§ They anchor themselves to other cells or fibrous structures at the wound margins
§ They slowly contract, drawing in the edges to reduce wound size
c. Original wound shape is different from resulting scar shape
1) This is due to the wound contraction process
2) Myofibroblasts contract at right angles to the wound’s margin
§ Square wound=X shaped scar
IV. Healing: The Major Tissues
A. Connective Tissues
*Limited blood supply=prolonged healing process
1. Bone
a. Osseous tissue has well-developed powers of regeneration
b. While bone is fractured, new bone tissue is formed and restores the original structure and
strength at the site of damage
c. Occurs in three stages
1) Step 1: Removal of clotted blood, bone fragments, and other tissue debris
§ Bleeding into the gap between the bone ends and surrounding muscle mass
§ Granulation tissue forms and becomes organized
§ Capillaries develop from undamaged vessels
§ Osteoblasts are activated and migrate to the damage site
2) Step 2: Laying down collagen deposits and cartilage
§ Fibrocartilaginous mass spans the break and provides early stabilization of the fracture; forms
osteoid
§ Osteoid= “soft callus”
§ Ossification occurs by osteoblasts to form spongy bone (hard callus)
1. This is weak and locally enlarges the bone at the fracture site
3) Step 3: Remodeling of the hard callus
§ This restores the characteristic architecture of normal bone
§ Osteoblasts and osteoclasts build up and break down the hard callus, modeling the bone to
finally restore its normal structure
§ Then periosteum restoration occurs
2.Tendon/Ligament
a. This is usually successful where relatively regular edges can be closely approximated and
tightly sutured
b. Fibroblasts then produce densely-packed collagen bundles to restore tensile strength
c. Scar tissue forms in any irregular, roughened surfaces
1) This makes for a weaker union with less tensile strength and reduced functional capacity
3.Cartilage
a. Heals by fibrous repair
b. Scar tissue is supplied by fibroblasts from perichondrium
c. Scarring can produce some function loss
4.Adipose Tissue
a. The precursor cells are able to produce new replacement tissue if damage occurs
B. Epithelial Tissue
1.Epithelia are labile
2.Regeneration occurs at body surface, mucous membranes, and many other epithelial surfaces
a. EXCEPTION: epithelium of respiratory surface
1) Regeneration can occur of the damage is superficial, but NOT if the basement membrane is
damaged or if the ECM is disrupted
§ This would lead to scar formation
C. Glandular Tissue
1.Most glands are formed of stabile tissue
a. EXAMPLE: liver
1) Complete restoration has been noted even when 90% of the liver has been
damaged/removed
2.When tissue damage is extensive, regenerated tissue may vary from the norm
a. Causes some functional loss
b. EXAMPLE: kidney
1) Glomerular or Bowman’s capsule cells are unable to be replaced
3.Severe injury can damage ECM, stroma, and parenchymal cells
a. Lost tissue is replaced by a smaller volume of dense scar tissue
b. Produces an irregular surface pattern
1) EXAMPLE: glomerulonephritis of the kidney (Figure 4.15)
4.Exceptions include:
a. Parathyroid glands possess minimal regenerative capacity
b. Adrenal medulla and posterior pituitary: unable to produce new functional cells
1) Due to their derivation form nervous tissue, which is permanent
D. Nervous Tissue
1.Neurons are permanent cells (no mitosis is possible after birth)
a. Damaged neurons are replaced by gliosis (the proliferation of neuroglia)
b. Provide support, phagocytosis, and repair functions similar to white blood cells
2.In CNS
a. If the cell body remains intact, some initial regeneration of axons may occur
1) After 10-14 days, the proliferating glial cells form a scar-like mass that blocks any further
growth
b. No function can be restored by this partial and inadequate axon regeneration
3.In PNS
a. When only part of a myelinated neuron process is lost through damage, the lost portion can
regenerate if the supporting CT and Schwann cells remain intact along the original path of the
neuron process
1) Schwann cell is more resistant to injury than is the neuron process
b. A tuft of newly formed sprouts grows out of the proximal end of the process
1) This pattern is relatively slow and may take weeks to complete
2) It cannot replace any specialized sensory receptors
3) Results in loss of sensation
c. As long as the endoneural tube is intact, axons will regenerate
d. Traumatic neuroma: separated nerve endings result in the distal processes to degenerate
1) New regenerating processes emerge from the severed nerve stump and grow into the scar
tissue
E. Muscle Tissues
1.Skeletal and cardiac muscle are permanent
2.Healing is accomplished through fibrous repair (scarring)
a. Loss of function
b. Remaining cells increase in size and strength
3.In smooth muscle, mitotic capability is limited
a. EXCEPTION: Uterine wall
V. Complications of Healing
A. Contracture
1.When damage is extensive, newly formed collagen demonstrates exaggerated wound
contraction
2.This can also lead to tissue distortion and mobility limits
a. EXAMPLE: widespread skin burns
1) Cause substantial disfiguration
3.In repair of damage to the walls of tubular organs, stricture (narrowing of organ’s lumen) occurs
a. Consequences: normal motion of the organ contents is slowed or stopped
1) This is the cause of much infertility in women
B. Adhesions
1.Result of the organization of inflammatory exudate between serous membranes
a. Produces a firm union of the two membranes
b. Restricts movement
1) EXAMPLE: heart, lung, or abdominal organs develop adhesion after surgery
C. Dehiscence
1.The breaking open of a healing wound
a. Cause: pressure applied to the healing tissues interferes with the development of normal
strength
b. EXAMPLE: abdominal wall
2.Risks:
a. Exposure of the abdominal contents to infection
b. Loop of intestine is squeezed into the open wound, threatening blood supply
c. Herniation=displacement of an organ from its normal position
D. Keloids
1.Irregular masses of scar tissue that protrude from the surface of the skin
a. Result from overproduction of dermal collagen during healing
b. Could be due to excessive release of a particular growth factor, TGF-B
E. Proud Flesh
1.Overproduction of granulation tissue
2.Interferes with surface restoration
F. Suture Complications
1.At the surface, where the suture material enters the skin, the epithelium is interrupted
a. This stimulates mitosis and migration, but the cells cannot spread across the suture
b. Instead, they migrate into the dermis
c. When the sutures are removed, most of the new epithelium is carried off with the suture
2.What can go wrong:
a. Keratin can be sealed within the suture tract, deep within the dermis
b. This causes a pronounced fibrosis (scarring) in the dermis
c. This explains the more prominent scarring seen at points where sutures have passed
through the skin
G. Therapy
1.Radiation and chemotherapy
a. Suppress mitosis of cancer cells AND regular cell healing
2.Inflammatory Drugs
a. Interfere with protein synthesis, wound contraction, and regeneration of new epithelium
VI. Requirements for Healing
A. Clearance of Debris
1.Decreases likelihood for infection and healing delay
B. Immobility
1.Movement near wound edges delays healing
a. Interferes with the joining of tissues across the damaged area
2.Non-Union (Fibrous Union)
a. Fibrocartilaginous mass resembling osteoid is formed, but does not ossify
b. This tissue is much weaker
3.Nerve and tendon regeneration
a. Accurate alignment is necessary
C. Blood Supply
1.Delivery of oxygen to healing area
2.Many healing problems in elderly adults is a result of inadequate blood supply
D. Nutrients
1.Dietary protein deficiency will depress the healing response if prolonged
2.Vitamin C=collagen formation
3.Copper=cross-linking with collagen
VII. Control and Regulation of Healing
A. Growth factors
1.Promote growth
B. Growth Inhibitors
1.Oppose growth
C. Together, these regulate the processes vital to normal healing
1.Fibroblast migration, vessel formation, and collagen formation
D. ECM
1.Affect proliferation and migration and differentiation
E. Physical Contact and Barriers
1.When dividing cells contact each other, mitosis stops (contact inhibition)
a. This only occurs when the cells coming in contact with each other are the same type of cell

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