PATHOLOGY

Inflammation and Repair:

Inflammation
Dr. Teresita P. Bailon
OUTLINE
I.
Definition of Terms
II. Inflammation
III. Acute Inflammation
IV. Chronic Inflammation
V. Systemic Effects of Inflammation
VI. Consequences of Excessive/Defective
Inflammation

DEFINITION OF TERMS
Edema
Excess of fluid in interstitial tissues or serous cavities
(in between tissues)
Can either be exudate or transudate
Exudation
Escape of fluid, proteins and blood cells from the vascular
system into the interstitial tissue or body cavities
Exudate
Inflammatory extra-vascular fluid with high protein
concentration and cellular debris and high specific gravity
Causes alteration in normal permeability of small blood
vessel in site of injury
Transudate
Fluid with decreased protein concentration (low protein
content), little or no cellular material and low specific gravity
Ultrafiltrate of blood plasma that results from hydrostatic
imbalance across vascular endothelium
EXUDATE versus TRANSUDATE

Capillary Permeability
Specific Gravity
Protein Content
Inflammatory Cells

EXUDATE
Increased
>1.02
> 1.5 g/dl
Present

TRANSUDATE
Normal
<1.012
< 1 g/dl
Absent

Pus
A purulent exudate
An inflammatory exudate rich in leukocytes (neutrophils) and
parenchymal cell debris and microbes (in many cases)

INFLAMMATION
Reaction of vascularized living tissue to local injury
Complex reaction in tissues that consists mainly of responses
of blood vessels and leukocytes
Bodys principal defenders: Plasma proteins, circulating
WBCs & tissue phagocytes
Without inflammation Infection goes unchecked Wound
never heals Injured organ remains injured
Purpose: Destroy/dilute/wall off injurious agents (Protective
response)
Harmful effects: Brain edema can compromise respiratory
centers in the brain, deformity (rheumatic arthritis),
hypersensitivity reaction (e.g. Penicillin allergy)

Causes of Inflammation
1. Microbial infection
Most common and medically important
Among most important receptors for microbial products
are the family of Toll-like receptor ( TLRs)

SECTION B

June 21, 2011

2. Tissue necrosis
From ischemia, trauma and physical and chemical injury
Molecules known to elicit inflammation (from necrotic
cells): uric acid, ATP, HMGB-1 (DNA-binding protein).
Hypoxia also an inducer of inflammatory response due to
protein called HIF-1a.
3. Physical agents from thermal extremes or from ionizing
radiation, trauma
4. Chemical agents
5. Immunologic injury
Normally protective immune system damages the
individuals own tissues.
Note:
According to Robbins, listed above are the different
stimuli triggering ACUTE inflammatory reactions

Patterns of Inflammation
1. Acute
2. Subacute (Rarely seen)
3. Chronic
ACUTE vs. CHRONIC

ACUTE
Short
(weeks or days)

CHRONIC
Longer
(months to years)

Inflammatory
Edema

Present

Absent

Predominant
Cells

Polymorphonuclear
(ex: neutrophils)

Lymphocytes, plasma
cells, macrophages,
fibroblasts

Fibrosis/
Angiogenesis

Absent

Present

Duration

Components of Inflammation
1. Vascular Reaction
2. Cellular Reaction
a. Mediated by chemical factors derived from plasma
proteins
b. Terminated when offending agent is eliminated
Mediators are broken down or dissipated

ACUTE INFLAMMATION
Rapid host response that serves to deliver leukocytes and
plasma proteins to tissue injury/site of infection

Cardinal Signs of Acute Inflammation

1. Redness (RUBOR)
Vasodilation mediated by prostaglandins (PGE,
prostacyclin) causing hyperemia
2. Swelling (TUMOR)
Increased vascular permeability
Mediated by vasoactive amines histamine, serotonin
C3a, C5a, bradykinin, leukotrienes, C4, D4, E4, & platelet
activating factor PAF Edema
3. Heat (CALOR)
Warmth due to increased blood flow (hyperemia)

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4. Pain (DOLOR)
Increased pressure exerted by edema and stimulation of
pain-sensitive nerve endings by prostaglandin &
bradykinin
5. Loss of function (FUNCTIO LAESA)
Due to pain and immobility
Ex.: Tonsillitis It is difficult to swallow because it is
painful (motion of swallowing is limiting)

3 Major Components
1.
2.
3.

Alterations in vascular calibre that lead to an increase in

blood flow
Structural changes in the microvasculature that permit
plasma proteins and leukocytes to leave the circulation
Emigration of the leukocytes from microcirculation,
accumulation in focus of injury and activation to eliminate
offending agent.

Vascular Events of Acute Inflammation

Brief period of vasoconstriction

Vasodilatation

Increase in blood flow

Increase in hydrostatic pressure (capillaries, venules)

Transudate
A. Vasoactive Changes (Caliber and Flow)
1. Brief period of vasoconstriction (in seconds) which is
the natural response of the body to an injurious stimulus
or agent
2. Then, vasodilation (one of the earliest manifestations of
acute inflammation) of the arterioles (to capillary beds)
would occur resulting to increased blood flow (hallmark of
early hemodynamic change) causing heat and redness.
This is induced notably by histamine & NO.
3. There will be an increase in hydrostatic pressure of
the capillary venules. Also loss of fluid and increase
vessel diameter Slower blood flow & increase viscosity
of blood leasing to stasis (vascular congestion or
localized redness)
4. Then Transudation, the accumulation of neutrophils
along vascular endothelium.
B. Increased Capillary Permeability (Vascular Leakage)
Structural changes in the microvasculature permit the
plasma proteins and leukocytes to leak out of the vessels
and leave the circulation.
A hallmark of acute inflammation which results to edema
Mechanisms:
a. Endothelial cell contraction resulting in increased
interendothelial spaces is the most common
Elicited by histamine, bradykinin,leukotrienes,
neuropeptide substance P, etc.
Called immediate transient response (occurs rapidly,
short-lived 15-30mins)
b. Direct endothelial injury resulting in endothelial cell
necrosis and detachment which is rapid and may be
long-lived
i. Immediate sustained response
ii. Delayed prolonged response (e.g. sunburn; type IV
hypersensitivity reaction)

SECTION B

c. Leukocyte mediated endothelial injury via release of

toxic oxygen species and proteolytic enzymes
Association with late stages of inflammation
Long- lived
d. Increased transcytosis, which is the increased transport
of fluids & proteins
May involve channels called vesiculovacuolar
organelle located close to intercellular junctions
Induced by VEGF (vascular endothelial growth
factor)
C. Increased vascular permeability
Emigration of leukocytes from the microcirculation and the
accumulation in the focus of injury and their activation to
eliminate injurious/offending agent
Leads to exudate, which is a hallmark of acute
inflammation.
Changes in vascular flow and caliber
Vasodilation
Increased permeability of microvasculature
Stasis (vascular congestion)
Leukocytes (neutrophils) accumulate along
vascular endothelium
Increased Vascular Permeability (vascular leakage)
Endothelial cell contraction resulting in increased
interendothelial spaces
Endothelial injury, resulting in endothelial cell
necrosis and detachment
Transcytosis
Responses of Lymphatic Vessels
Increased lymph flow Drainage of edema fluid
Proliferation of lymphatic vessels
Lymphangitis Inflamed lymphatics
Lymphadenitis Inflamed lymph nodes

Inc. vascular permeability Exudate

Hemoconcentration

Decrease I.V. osmotic pressure

(With increase HP due to vasodilation)

Increase blood viscosity

Stasis

Edema (swelling)

Disrupts normal axial flow

CELLULAR EVENTS OF ACUTE INFLAMMATION

Cellular Events of Acute Inflammation

Extravasation Journey of leukocytes from the vessel lumen

to the interstitial tissue. Divided into following steps:
1. Margination: Occurs as leukocytes localize to the outer
margin of the blood flow adjacent to the vascular
endothelium
2. Rolling: Leukocytes tumble slowly along the endothelium
and adhere transiently and finally come to rest where
they adhere firmly

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3. Adhesion: Adhesion molecules on the surfaces of both

endothelial cells and leukocytes. Mediated by
complementary adhesion molecules leading to
expression, enhanced by cytokines.
3 molecular families of adhesion receptors:
i. Selectins (E, L, P)
Mediates initial rolling interactions
E(endothelium), L (leukocytes), P (platelets &
endothelium)
ii. Igs (ICAM-1, VCAM-1)
iii. Integrins
Note:
TNF and IL-1 induce endothelial expression of ligands for
integrins, mainly VCAM-1 and ICAM-1)
4. Diapedesis: Transmigration across the endothelium
involving Ig (CD31 and PECAM)
Occurs mainly in post-capillary venules
Chemokines act on leukocytes & stimulate cells to
migrate toward site of injury
Adhesion molecules involved: PECAM or CD31
Leukocytes retain at site where they are needed due
to integrins and CD44
5. Chemotaxis: Purposeful and unidirectional movement of
leukocytes toward the site of injury or migration toward a
chemotactic stimulus
Chemotactic factors:
i. Bacterial products
Most common exogenous agents
Includes peptides that possess an Nformylmethionine terminal amino acid
ii. Complement components (C5a) [endogenous]
iii. Arachidonic acid metabolites (LTB4) [endogenous]
iv. Cytokines (IL-8) [endogenous]
Note:
Neutrophils predominate in inflammatory infiltrate during
first 6-24 hours, and replaced by monocytes in 24-48 hours
Table 2.1. Endothelial-Leukocyte Adhesion Molecules

Endothelial
Molecule
P-selectin

E-selectin

Leukocyte
Molecule
Sialyl-Lewis
Xmodified
proteins
Sialyl-Lewis
Xmodified
proteins

GlyCam-1, CD34

L-selectin **

ICAM-1
(immunoglobulin
family)

CD11/CD18
(2) integrins
(LFA-1, Mac1)

VCAM-1
(immunoglobulin
family)

VLA-4 (1)
integrin

Major Role
Rolling
(neutrophils, monocytes,
T lymphocytes)
Rolling and adhesion
(neutrophils, monocytes,
T lymphocytes)
Rolling
(neutrophils, monocytes)
Adhesion, arrest,
transmigration
(neutrophils, monocytes,
lymphocytes)
Adhesion
(eosinophils, monocytes,
lymphocytes)

** - L-selectin is expressed weakly on neutrophils. It is involved in

the binding of circulating T-lymphocytes to the high endothelial
venules in lymph nodes and mucosal lymphoid tissues, and
subsequent homing of lymphocytes to these tissues.

SECTION B

Recognition of Microbes and Dead Tissues

Once recruited, leukocytes must be activated to perform
their functions. Responses of leukocytes consist of two
sequential events:
1. Recognition of the offending agents which deliver
signals
2. These signals then activate the leukocytes to ingest
and destroy offending agents and amplify the
inflammatory action
Receptors that recognize external stimuli and deliver
signals:
Receptors for microbial products (TLRs) Present on cell
surface and in endosomal vesicles of leukocytes
GPCR Found on neutrophils, macrophages which
recognize N-formylmethionyl residues on bacterial peptides;
others recognize chemokines, C5a, platelet activating factor,
prostaglandins and leukotrienes.
Opsonin Receptors Include antibodies (IgG), complement
proteins (C3) and lectins (mannan-binding lectin)
Cytokine Receptors Interferon- (IFN-) major
macrophage activating cytokine; secreted by NK cells and by
antigen-activated T-lymphocytes during adaptive immune
responses.

Removal of Offending Agents Phagocytosis

Ingestion of particulate material (ex: tissue debris, living or
dead bacteria, other foreign cells) by phagocytic cells
Neutrophils and monocytes-macrophages most important
phagocytic cells
3 Sequential steps:
1. Recognition and attachment
Involves:
Mannose receptors
A lectin that binds terminal mannose and
fucose of glycoproteins and glycolipids
Recognize microbes and not host cells
Scavenger receptors (sr)
Bind and mediate endocytosis of oxidized or
acetylated LDL receptor particles that can no
longer interact with the conventional LDL
receptor
E.g. Macrophage sr & macrophage intergrins
[Mac-1 (CD 11b/CD18)]- also bind microbes for
phagocytosis
Receptors for opsonins
Opsonization: process of coating a particle by
opsonins to target it for ingestion; facilitates
phagocytosis
3 major opsonins:
1. Fc fragment of IgG (Naturally occurring
Ab against the ingested particle)
2. C3b from complement activation via
immune or non-immune mechanisms
3. Plasma lectins Mannan-binding lectin
(MBL)
2. Engulfment
1. Phagosome Vesicle that encloses the particle (after
being bound to phagocyte receptors)
2. Phagolysosome Fusion of phagosome and
lysosomal granules
3. Degranulation Discharge granules from lysosome
into phagolysosome
4. Regurgitation
Proteolytic enzymes leak
Tissue damage

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3. Microbial Killing and Degradation

Within phagocytic cells neutrophils and macrophages
Mediated by:
a. Oxygen-dependent microbial killing
H2O2 myeloperoxidase and halide system
Main mechanism
Most effective/efficient bactericidal system of
neutrophils
Mostly by ROS (Superoxide Hypochlorite
and OH radical) and reactive nitrogen
species (NO Peroxynitrite)
ROS Generated due to activation of
NADPH oxidase which oxidizes NADPH
which reduces oxygen to superoxide anion
Superoxide anion is then converted to
hydrogen peroxide.
H2O2 is converted to hypochlorite by
myeloperoxidase (MPO) in presence of
halide (Cl ).
Hypochlorite Potent antimicrobial agent,
destroys by halogenation or by oxidation of
proteins and lipids.
NO Produced from arginine by nitric oxide
synthase; it reacts with superoxide to
generate free radical peroxynitrite which
damage lipids, proteins and nucleic acids of
microbes
b. Oxygen-independent microbial killing
Less effective
Mediated by bacterial permeability
increasing protein (BPI) [binds bacterial
endotoxin], lysozyme [hydrolyzes muramic
acid N-acetylglycosamine bond], lactoferrin,
major basic protein (MBP) [cationic protein
of eosinophils, cytotoxic to parasites],
defensins [arginine-rich granule peptides],
cathelicidins
Other Functional Responses of Activated Leukocytes
Macrophages
Produce growth factors that stimulate proliferation of
endothelial cells and synthesis of collagen and enzymes
that remodel connective tissues
Products drive process of repair
a. CLASSICALLY ACTIVATED Macrophages
Respond to microbial products and T-cell cytokines
such as IFN-, have strong microbicidal activity
b. ALTERNATIVELY ACTIVATED Macrophages
Respond to cytokines IL-4 AND IL-13, mainly
involved in tissue repair and fibrosis.

Table 2-2 Clinical Examples of Leukocyte-Induced Injury

Disorders

Cells and Molecules Involved in Injury

ACUTE

Acute respiratory distress

syndrome

Neutrophils

Acute transplant rejection

Lymphocytes; antibodies and

complement

Asthma

Eosinophils; IgE antibodies

Glomerulonephritis

Neutrophils, monocytes; antibodies and

complement

Septic shock

Cytokines

Lung abscess

Neutrophils (and bacteria)

CHRONIC

Arthritis

Lymphocytes, macrophages;
antibodies?

Asthma

Eosinophils; IgE antibodies

Atherosclerosis

Macrophages; lymphocytes?

Chronic transplant rejection

Lymphocytes; cytokines

Pulmonary fibrosis

Macrophages; fibroblasts

Table 2-3 Defects in Leukocyte Functions

Disease

Defect
GENETIC

Inherited defects in leukocyte adhesion

Leukocyte adhesion
deficiency 1

Defective leukocyte adhesion because

of mutations in chain of CD11/CD18
integrins

Leukocyte adhesion
deficiency 2

Defective leukocyte adhesion because

of mutations in fucosyl transferase
required for synthesis of sialylated
oligosaccharide (ligand for selectins)

Inherited defects in microbicidal activity

Chronic granulomatous
disease
X-linked
Autosomal recessive

MPO deficiency

Decreased oxidative burst

Phagocyte oxidase (membrane
component)
Phagocyte oxidase (cytoplasmic
component)
Decreased microbial killing because of
defective MPOH2O2 system

Inherited defects in phagolysosome function

Fig. 2-10. Subsets of Activated Macrophages

Chdiak-Higashi
syndrome

Decreased leukocyte functions because

of mutations affecting protein involved in
lysosomal membrane traffic
*autosomal recessive; defective fusion
of phagosomes and lysosomes;
abnormalities in melanocytes (albinism),
nerve cells and plateletes
ACQUIRED

SECTION B

Bone marrow suppression:

tumors, radiation, and
chemotherapy

Production of leukocytes

Diabetes, malignancy,
sepsis, chronic dialysis

Adhesion and chemotaxis

Leukemia, anemia, sepsis,

diabetes, malnutrition

Phagocytosis and microbicidal activity

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Types of Inflammatory Cells

Viral infections Lymphocytes (First 24 hours)
Hypersensitivity reactions Eosinophils
Neutrophils
Cells are the common inflammatory cells found in acute
response
Manifested in the first 6-24 hours of an inflammatory
response
Exceptions
Pseudomonal infections Neutrophils for 2-4 days
Viral infections Lymphocytes
Hypersensitivity reactions Eosinophils
Monocytes, Macrophages
Replaces neutrophils after 1-2 days (Dominant in chronic
inflammation)
Components of mononuclear phagocyte system
Accumulate in response to
Continued recruitment of monocytes from the circulation
Local proliferation (Mitosis) of macrophages after
emigration
Prolonged survival and immobilization of macrophages
within inflamed tissue
Examples of macrophages: Kupffer cells (liver), Sinus
histiocytes (spleen and lymph nodes), Alveolar macrophages
(lungs), Microglia (central nervous system)
Activated macrophages eliminate injurious agents and
initiate process of repair
Activated macrophages induce tissue destruction (One of
hallmarks of chronic inflammation)
Lymphocytes
Viral infections
Associated with chronic inflammation together with
monocytes-macrophages and plasma cells
Mobilized in antibody and cell-mediated immunologic
reaction and in non-immunologic reaction
Activated lymphocyte (Activated by contact with antigen)
Produces lymphokines Stimulates monocyte chemotaxis
+ activation of macrophages Activated macrophages
produce monokines Monokines influence T- and B-cell
functions
Activated T-lymphocytes produce cytokines which also
recruits IFN- a powerful activator of macrophages. This
could make inflammatory reaction chronic and severe
Eosinophils
Cells are seen in allergic reactions (IgE-mediated) and
parasitic infections
Orange to reddish granules
Granules contain MBP toxic to parasites and cause lysis of
epithelial cells resulting in tissue damage in hypersensitivity
reactions
Plasma Cells
Develop from activated B lymphocytes
Produce antibody (Ab) against the antigens in inflammatory
site or versus Altered tissue component
May assume features of lymphoid organs (called tertiary
lymphoid organs) together with lymphocytes and antigenpresenting cells
Seen in synovium of patients with rheumatoid arthritis
Basophils
Prominent dark purple granules
Cytoplasmic inclusion

SECTION B

Mast Cells
Participate in both acute and chronic inflammatory reactions
Express the receptor (FcRI) that binds the Fc portion of IgE
antibody
Specialized cells with cytoplasmic granules (histamine)
Histamine are released in response to type I hypersensitivity
reactions

Factors that Modify the Inflammatory Response

1. Nature and intensity of injury
2. Site and tissue affected
3. Hosts response
Nutrition
Adequacy of CVS
Drug treatment
Other diseases (D.M., cancer)
Previous immunity to agent

2nd line of Defense in Acute Inflammation

MPS and Lymphatics
MPS: Mononuclear Phagocyte System
Lymphangitis (Inflammation of lymph vessels)
Reactive or inflammatory lymphadenitis (Lymph nodes)
Bacteremia: Bacteria in blood (Heart valves, meninges,
kidneys, and joints)

Mediators of Inflammation
A. Cell-derived mediators
1. Vasoactive amines: Histamine and Serotonin
Histamine is the principal mediator of immediate
transient phase of increased vascular permeability
Serotonin is stimulated when platelets aggregrate with
collagen, thrombin, ADP, antigen-antibody complexes
2. Arachidonic Acid Metabolites: Prostaglandins,
Leukotrienes and Lipoxins
Prostaglandins is produced by COX-1 and COX-2
Most important: PGE2, PGD2, PGF2, PGI2
(Prostacyclin) & TxA2 (Thromboxane)
Leukotrienes is produced by lipoxygenase enzymes,
5-lipoxygenase, predominant in neutrophils and is
more potent than histamine in increasing vascular
permeability
Lipoxins inhibit leukocyte recruitment and cellular
components of inflammation
3. Platelet-activating factor (PAF)
4. Reactive Oxygen species
Causes endothelial cell damage, injury to other cell
types, inactivation of antiproteases
5. Nitric Oxide (NO)
Dual actions in inflammation:
a. Contributes to vascular reaction
(Promotion of vasodilation)
b. Inhibits the cellular component of inflammatory
responses
6. Cytokines and Chemokines
Cytokines (IL-1 &TNF) induce systemic acute-phase
responses associated with infection or injury
Chemokines has 2 main functions:
a. Stimulate leukocyte recruitment in inflammation
b. Control normal migration of cells
4 major groups: C-X-C, C-C,C & CX3C chemokines

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7. Lysosomal Constituents of Leukocytes

Acid proteases Degrade bacteria within
phagolysosomes
Neutral proteases Degrade extracellular
components
8. Neuropeptides
Neurokinin A and substance P
Some functions: Transmission of pain signals,
regulation of BP & increasing vascular permeability
Table 2-4. The Actions of the Principal Mediators of Inflammation

Mediator

Principal
Sources

Actions

CELL-DERIVED
Histamine

Mast cells,
basophils,
platelets

Vasodilation, increased vascular

permeability, endothelial activation

Serotonin

Platelets

Vasodilation, increased vascular

permeability

Prostaglandins

Mast cells,
leukocytes

Vasodilation, pain, fever

Leukotrienes

Mast cells,
leukocytes

Increased vascular permeability,

chemotaxis, leukocyte adhesion and
activation

Plateletactivating factor

Leukocytes,
mast cells

Vasodilation, increased vascular

permeability, leukocyte adhesion,
chemotaxis, degranulation, oxidative
burst

Reactive
oxygen species

Leukocytes

Killing of microbes, tissue damage

Nitric oxide

Endothelium,
macrophages

Vascular smooth muscle relaxation,

killing of microbes

Cytokines
(TNF, IL-1)

Macrophages,
endothelial
cells, mast cells

Local endothelial activation

(expression of adhesion molecules),
fever/pain/anorexia/hypotension,
decreased vascular resistance
(shock)

Chemokines

Leukocytes,
activated
macrophages

Chemotaxis, leukocyte activation

PLASMA PROTEINDERIVED
Complement
products (C5a,
C3a, C4a)

Plasma
(produced in
liver)

Kinins

Plasma
(produced in
liver)

Proteases
activated during
coagulation

SECTION B

Plasma
(produced in
liver)

Leukocyte
chemotaxis and
activation,
vasodilation (mast
cell stimulation)

Fig. 2-13 Principal Local and Systemic Actions of TNF and IL-1

B. Plasma Protein-derived mediators

1. Complement system
Critical steps in complement activation:
Proteolysis of C3.
Cleavage of C3 can occur in 3 pathways:
a. Classical pathway
b. Alternative pathway
c. Lectin pathway
All lead to formation of C3 convertase, which
splits C3 into distinct fragments, finally
culminating into formation of membrane attack
complex (MAC)
Biologic functions:
a. Inflammation [C3a, C5a, C4a]
b. Phagocytosis [C3b]
c. Cell lysis [MAC]
2. Coagulation and Kinin systems
Kinins are vasoactive peptides derived from plasma
proteins called kininogens by proteases called
kallikreins
Activated Hageman factor (Factor XIIa) initiates four
systems involved in inflammatory response:
a. Kinin system [Produces vasoactive kinins]
b. Clotting system [Thrombin formation]
c. Fibrinolytic system [Produces plasmin and
degrades fibrin]
d. Complement system [Produces anaphylatoxins]

Increased vascular
permeability, smooth
muscle contraction,
vasodilation, pain
Endothelial activation,
leukocyte recruitment

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Table 2-7. Role of Mediators in Different Reactions of Inflammation

Role in Inflammation

Mediators
Prostaglandins

Vasodilation

Nitric oxide
Histamine
Histamine and serotonin
C3a and C5a (by liberating vasoactive
amines from mast cells, other cells)

Increased vascular
permeability

Bradykinin
Leukotrienes C4, D4, E4
PAF
Substance P
TNF, IL-1

Chemotaxis,
leukocyte
recruitment and
activation

Chemokines
C3a, C5a
Leukotriene B4

Fever

IL-1, TNF

Pain

Prostaglandins
Bradykinin

Tissue damage

Lysosomal enzymes of leukocytes

Reactive oxygen species
Nitric oxide

b. Myeloperoxidase deficiency
i. Associated with recurrent infections, but has little
consequence
c. Chediak-Higashi syndrome
i. Autosomal recessive disorder
ii. Marked by the presence of abnormal WBC
iii. Neutropenia, albinism, cranial and peripheral
neuropathy and a tendency to repeated infections

Morphologic Patterns of Acute Inflammation

Based on the nature of exudates
Hallmarks of Acute Inflammation
a. Dilation of small blood vessels
b. Slowing of blood flow
c. Accumulation of leukocytes and fluid in the extravascular
tissue

Serous Inflammation
Fluids predominate
Marked by the outpouring of a thin fluid that may be derived
from the plasma or from the secretions of mesothelial cells
lining the peritoneal, pleural and pericardial cavities
Effusion: Accumulation of fluid in the cavities
Ex: Skin blisters from a burn or viral infection

Outcome of Acute Inflammation

Complete Resolution
Clearance of injurious stimuli
Involves removal of cellular debris and microbes by
macrophages, and resorption of edema fluid by lymphatics
Injury must be short-lived or when there has been little tissue
destruction and the damaged parenchymal cells can
regenerate
Restoration of the site of acute inflammation to normal
Healing By CT Replacement (Fibrosis or Scarring)
After substantial tissue destruction
Involves tissues that are incapable of regeneration, or when
there is abundant fibrin exudation in tissue or serous cavities
(pleura, peritoneum) that cannot be adequately cleared
Organization: CT grows into the damaged/exudated area
converting it into a mass of fibrous tissue
Collagen deposition
Loss of function
Progression to Chronic Inflammation
When the acute inflammatory response cannot be resolved
due to:
Persistence of the injurious agent
Interference with the normal process of healing

Serous inflammation. Low-power view of a cross-section of a skin blister showing

the epidermis separated from the dermis by a focal collection of serous effusion.

Fibrinous Inflammation

More of plasma proteins (fibrinogen) and fibrin (thread-like or

solid amorphous eosinophilic coagulum)
A greater increase in vascular permeability causes large
molecules such as fibrinogen to pass the vascular barrier
Fibrin is formed and deposited in the extracellular space
Characteristic of inflammation in the lining of body cavities
meninges, pericardium, pleura
Histologically, fibrin appears as an eosinophlic meshwork of
threads or an amorphous coagulum
If fibrin is no removed, it may stimulate the ingrowth of
fibroblasts and blood vessels, leading to scarring
E.g. bread and butter pericarditis; meninges

Hereditary Defects:
Impairment of Acute Inflammatory Response

A. Deficiency of Complement Components

a. Increased susceptibility to infection
b. Deficiency of factors C2, C3, and C5
B. Defects In Neutrophils
a. Chronic granulomatous disease of childhood
i. X-linked disorder
ii. Due to deficient activity of NADPH oxidase

SECTION B

Fibrinous pericarditis.
A. Deposits of fibrin on the pericardium.
B. A pink meshwork of fibrin exudate (F) overlies the pericardial surface (P).

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Suppurative/Purulent Inflammation
Production of large amounts of pus or purulent exudate
consisting of neutrophils, liquefactive necrosis & edema fluid
Pyogenic bacteria: pus producing
Ex: Acute appendicitis
Abscesses: Localized collections of pus (neutrophils,
necrotic cells and edema fluid) buried in tissue, organ or a
confined space. Usually caused by pyogenic organisms
o Central region: A mass of necrotic leukocytes and tissue
cells

The morphology of an ulcer.

A. A chronic duodenal ulcer.
B. Low-power cross-section of a duodenal ulcer crater with an acute inflammatory
exudate in the base.

CHRONIC INFLAMMATION
Inflammation of prolonged duration (weeks or months) in
which inflammation, tissue injury, and attempts at repair
coexist, in varying combinations

Causes
Purulent inflammation.
A. Multiple bacterial abscesses in the lung, in a case of bronchopneumonia.
B. The abscess contains neutrophils and cellular debris, and is surrounded by
congested blood vessels.

Membranous Inflammation

Necrosis of mucosa and inflammatory exudate remain

attached as surface membrane
E.g. Diphtheria, membranous enterocolitis

Ulcers
A local defect, or excavation, of the surface of an organ or
tissue
Produced by the sloughing/shedding of the inflamed necrotic
tissue
Only occurs when necrosis/inflammation exist on/or near
surface
Found in:
i. Mucosa of the mouth, stomach, intestines, or
genitourinary tract
ii. Skin and subcutaneous tissue of the lower extremities
Intense polymorphonuclear infiltration and vascular dilation in
the margins of the defect
Best exemplified by peptic ulcer of stomach and duodenum
Prolonged ulcers develop
iii. Fibroblastic proliferation
iv. Scarring
v. Accumulation of lymphocytes, macrophages & plasma
cells

SECTION B

1. Persistent infections by microorganisms difficult to

eradicate (TB, T.pallidum, virus, fungi, parasites) Delayed
hypersensitivity rxn Granulomatous reaction
2. Prolonged exposure to non-degradable toxic substances
Asbestosis, silicosis, atherosclerosis [by endogenous toxic
plasma lipids]
3. Immune-mediated inflammatory disease
a. Autoimmune diseases (immune rxn against own tissues
evoked by autoantigens)
Rheumatoid arthritis, multiple sclerosis
b. Unregulated immune response against microbes
Inflammatory bowel disease
c. Immune rxn against environmental allergens
Bronchial asthma

Histiologic Hallmarks of Chronic Inflammation

1. Mononuclear cell infiltration
2. Proliferation of fibroblasts and small blood vessels
(neovascularisation/angiogenesis)
3. Increased connective tissue (fibrosis)
4. Tissue destruction

Patterns of Chronic Inflammation

Non-granulomatous
Diffuse proliferation of chronic inflammation cells, fibroblasts
and collagen
Granulomatous
Granulomas
A focus of chronic inflammation consisting of a microscopic
aggregation of macrophages that are transformed into
epithelium-like cells surrounded by a collar of mononuclear
leukocyte, principally lymphocytes
Nodular collections of specialized macrophages referred to
as epitheliod cells (modified macrophages resembling
epithelial cells) surrounded by a rim of lymphocytes,
multinucleate giant cells, +/- caseous necrosis
Histologically: Epitheloid cells have pale pink granular
cytoplasm, indistinct cell boundaries; nucleus: less dense,
oval or elongate, folding of nuclear membrane; may fuse to
form giant cells

UERMMMC Class 2014: Malubay, Ramas, Ramos, Palileo

Pathology 8 | 10

 Formation involves activation of macrophages by

interactions with T lymphocytes
Macrophage present poorly digestible antigen to CD4 +
lymphocytes. Interaction with the antigen specific T-cell
receptor of these cells triggers the release of cytokines
(esp. interferon), which mediate the transformation of
monocytes and macrophages to epitheliod and giant
cells (Langhans/foreign body)
2 Types:
a. Foreign body
Talc, sutures, fibers are large enough to produce
phagocytosis by a single macrophage
Do not incite specific inflammatory responses
b. Immune granuloma
Insoluble particles induce cell- mediated immune
response
Causes
1. Infectious agents
a. Bacterial TB, SY, leprosy, cat-scratch disease
(Gm bacillus)
b. Fungal Cryptococcus, Coccidioides immitis
c. Parasitic Schistosomiasis
2. Inorganic materials and dusts Silicosis, berylliosis,
irritant lipids
3. Unknown etiology sarcoidosis (E.g. Crohn disease)
Table 2-8. Examples of Diseases with Granulomatous Inflammation

Disease

Tuberculosis

Cause

Tissue Reaction

Mycobacterium
tuberculosis

Caseating granuloma (tubercle):

focus of activated macrophages
(epithelioid cells), rimmed by
fibroblasts, lymphocytes,
histiocytes, occasional Langhans
giant cells; central necrosis with
amorphous granular debris; acidfast bacilli

Leprosy

Mycobacterium
leprae

Acid-fast bacilli in macrophages;

noncaseating granulomas

Syphilis

Treponema
pallidum

Gumma: microscopic to grossly

visible lesion, enclosing wall of
histiocytes; plasma cell infiltrate;
central cells necrotic without loss
of cellular outline

Cat-scratch
disease

Gram-negative
bacillus

Rounded or stellate granuloma

containing central granular debris
and recognizable neutrophils;
giant cells uncommon

Sarcoidosis

Unknown
etiology

Noncaseating granulomas with

abundant activated macrophages

Immune reaction
Crohn disease
against intestinal
(inflammatory
bacteria, selfbowel disease)
antigens

Occasional noncaseating
granulomas in the wall of the
intestine, with dense chronic
inflammatory infiltrate

SYSTEMIC EFFECTS OF INFLAMMATION

Acute Phase Response or Systemic Inflammatory Response
(SIRS)
Changes that are associated with acute inflammation are
called ACUTE PHASE RESPONSE
The acute phase response consists of several changes
namely:
1. Fever
2. Acute Phase Proteins
3. Leukocytosis
4. Other responses

SECTION B

Fever

Characterized by an increase in body temperature usually by

1 to 4 C
One of the most prominent manifestation of the acute
response
This is produced in response to PYROGENS
o These substances stimulate prostaglandin synthesis
(especially PG2) in the hypothalamus
Increases production of cAMP Reset temperature
set point at higher level
Bacterial products, such as LPS (exogenous pyrogens)
stimulate leukocytes to release of cytokines, such as IL-1 and
TNF (endogenous pryogens) that increase the enzymes
(cyclooxygenases) that convert AA into PG
NSAIDs (Ex: asprin) diminish fever by inhibiting PG synthesis

Acute Phase Proteins

These are plasma proteins, mostly found in the liver, that

increase in concentration as response to inflammatory
stimulus
3 Kinds:
o C-reactive protein (CRP)
o Fibrinogen
Bind RBCs and forming stacks (rouleaux) that
sediment more rapidly than inidividual RBC
o Serum amyloid A (SAA)
Replace apolipoprotein A
Prolonged production causes secondary amyloidosis
Synthesized by hepatocyes and up-regulated by cytokines
o IL-6 for CRP and fibrinogen
o IL-1 or TNF for SAA

Leukocytosis
Commonly found in bacterial infections
Differ from Leukomoid Reaction
o Extreme increase in leukocytes
o No Blast cells seen
o Occurs initially because of accelerated release of cells
from bone marrow post mitotic pools
Prolonged infection causes proliferation of leukocyte
precursors from the bone marrow
o Bone marrow output is increased to compensate for the
inflammatory response
o Shift to the left Rise in number of more immature
neutrophils in blood
Neutrophilia
o Increase in neutrophil count in the blood
Eosinophilia
o Increase in eosinophil count in the blood
o Found in bronchial asthma, allergy and parasitic infections
Lymphocytosis
o Increase in lymphocyte count in the blood
o Found in viral infections such as infectious mononucleosis,
mumps and German measles
Leukopenia
o There is a decrease number of circulating white cells
o Associated with typhoid fever and infections caused by
some viruses, rickettsia, and protozoa

Other Acute-Phase responses

1. Increase ESR (Erythrocyte sedimentation rate)
Basis: Fibrinogen binds to red cells and causes them to
form stacks that sediment more rapidly at unit gravity than
individual red cells
2. Increase Blood Coagulability
Sticky platelet, coagulation factor

UERMMMC Class 2014: Malubay, Ramas, Ramos, Palileo

Pathology 9 | 10

ANSWERS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

Calor (Heat)
Transudate
Endothelial cell contraction
Extravasion
Chronic Granulomatous disease
Suppurative/purulent inflammation
Scarring/Fibrosis
Chronic Inflammation
Cryptococcus
Oxygen dependent microbial killing

3. Sepsis
In severe bacterial infections
Large amounts of organisms and LPS increase production
of cytokines
Results in IV coagulation, cardiovascular failure and
metabolic disturbance
Septic shock
Triad of DIC, hypoglycaemia and CVS failure)
ARDS (Adult Respiratory Distress Syndrome)
Multiple Organ Failure
4. Other manifestations: Increase pulse and BP, decreased
sweating, rigors, chills, anorexia, somnolence and malaise.

CONSEQUENCE OF DEFECTIVE OR EXCESSIVE

INFLAMMATION

Defective Inflammation

Results in increased susceptibility to infections

Inflammation response is central component of innate
immunity
Associated with delayed wound healing
Inflammation needed for removal of damaged tissues and
debris, and provides stimulus to start process of repair

Excessive Inflammation
Allergies
Autoimmune diseases
Cancer
Atherosclerosis
Ischemic heart
Alzheimer disease
Other chronic infectious and metabolic diseases.

REFERENCES
1. Dr. Bailons Lecture: Inflammation and Repair
2. Robbins Pathologic Basis of Disease
3. 2013B Trans: Inflammation and Repair

REVIEW QUESTIONS
1.

One of the cardinal signs of acute inflammation that deals

with warmth due to hyperaemia
2. Filtrate of blood plasma that results from hydrostatic
imbalance
3. It is the most common culprit in increase capillary
permeability
4. Journey of the WBC from the vascular to interstitial area
5. Hereditary defect in neutrophils that is due to deficient
activity of NADPH oxidase
6. Acute appendicitis is what type of acute inflammation
7. Healing by connective tissue replacement is also called
by_____?
8. Proliferation of fibroblast is one of the histologic hallmarks
of?
9. What causes fungal granulomatous chronic inflammation?
10. Most effective and main mechanism in killing microbes.

SECTION B

UERMMMC Class 2014: Malubay, Ramas, Ramos, Palileo

Pathology 10 | 10