CHAPTER 2

ACUTE AND CHRONIC INFLAMMATION

OVERVIEW OF INFLAMMATION
Inflammation
Ability to get rid of damage or necrotic tissues and foreign
invaders.
host response
a protective response designed to rid the organism of both
the
a.
initial cause of the cell injury (microbes, toxins) and the
b.
consequences of such injury
cardinal signs of inflammation:
1.
rubor
2.
tumor
3.
calor
4.
dolor
fifth clinical sign: function lasea (loss of function)
KEYPOINTS FOR INFLAMMATION

Inflammation is a complex reaction in tissues that consists

mainly of responses of blood vessels and leukocytes
the bodys principal defenders against foreign invaders are:
a.
plasma proteins and
b.
circulating leukocytes
c.
tissue phagocytes
The presence of proteins and leukocytes in the blood gives
them the ability to home to any site where they may be
needed.
Microbes and necrotic cells are present in tissues, outside
the circulation -> proteins and circulating cells have to be
rapidly recruited to these extravascular sites

The vascular and cellular reaction inflammation are triggered

by soluble factors that are produced by various cells or
derived from plasma proteins and are generated or activated
in response to the inflammatory stimulus
Inflammation may be acute or chronic
Acute inflammation

rapid onset

of short duration

;lasting for hours or days

main characteristics of acute inflammation are:

a.
exudation of fluid and plasma proteins
(edema)
b.
emigration of leukocytes, predominantly
neutrophils
Chronic inflammation

when acute inflammation response fails to clear

the invaders, it can progress to a chronic phase

may follow acute inflammation or be insidious in

onset.

of longer duration

associated with
a.
the
presence
of
lymphocytes
and
macrophage
b.
the proliferation of blood vessels
c.
fibrosis
d.
tissue destruction
Inflammation is terminated when the offending agent is
eliminated
The inflammatory response is closely intertwined with the
process of repair
Repair begins during inflammation but reaches completion
after the injurious influence has been neutralized.
The injured tissue is
a.
replaced through regeneration of native parenchymal
cell by
b.
filling of the defect with fibrous tissue (scarring)
c.
combination of both
Inflammation may be harmful in some situations
Inflammation may contribute to a variety of disease that are
not thought to be primarily due to abnormal host responses.

INFLAMMATION
FIVE CLASSICAL SIGNS
1. Changes in Blood Flow
Mechanism
o
Release of vasoactive peptides from damaged and
aggregating cells
Clinical Response

2.
-

3.
-

4.
-

5.
-

o
redness
o
heat
Permeability Changes
Mechanism
o
contraction of lining cells
o
widening of endothelial junctions
o
fluid leakage
o
sensory nerve irritation
Clinical Response
o
swelling and pain
Hemostasis
Mechanism
o
Local concentration of blood in capillaries and
venules
o
congestion
o
decreased blood flow leads to hypoxia
Clinical response
o
loss of function
WBC responses
Chemotaxis

Mechanism of Action
o
neutrophils
o
mononuclear cells
Phagocytosis

Mechanism of Action
o
WBCs identify, attack, ingest and dispose foreign
matter
o
Enzyme, O2 radicals, inflammatory mediators
o
Removal of noxious agents, tissue debris and fibrin
leads to further tissue damage

Clinical response: PAIN

Repair and Regeneration
Mechanism of Action
o
connective (scar) tissue formation
o
growth of new blood vessels
o
replacement of destroyed cells
clinical response
o
loss of function
ACUTE INFLAMMATION
rapid host response
serves to deliver leukocytes and plasma proteins
(antibodies) to site of infection
3 major components:
1.
alterations in vascular caliber - increase blood flow
2.
structural changes in the microvasculature
3.
emigration of the leukocytes from microcirculation

accumulation in the focus of injury

activation to eliminate the offending agent

STIMULI FOR ACUTE INFLAMMATION

acute inflammatory reactions may be triggered by a variety
of stimuli:
a.
Infections
as well as microbial toxins
most common causes of inflammation
important receptors for microbial products are:

TLRs (Toll-like receptors)

cytoplasmic receptors

engagement of these receptors triggers signaling

pathway that stimulate the production of various
mediators
b. Tissue necrosis
causes may include ischemia, trauma as well as physical and
chemical injury
molecules release form necrotic cells known to elicit
inflammation and includes:

uric acid

adenosine dipohosphate (ADP)

DNA binding protein called HMGB-1

DNA

Hypoxia - HIF-
c.
d.
-

Foreign bodies
elicit inflammation because they cause traumatic tissue
injury or carry microbes
immune reactions
hypersensitivity reactions
injurious immune response may be directed against

self-antigens causing autoimmune disease

CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION

may be excessive reactions against environmental

substances or microbes.
stimuli for inflammatory response cannot be eliminated ->
autoimmune reactions tend to be persistent
inflammation is induced by cytokines produced by Tlymphocytes

REACTION OF BLOOD VESSELS IN ACUTE INFLAMATION

Exudation
escape of fluid, proteins, and blood cells from the vascular
system into the interstitial tissue or body cavities
can involve:
a.
Exudate
o
extravascular
fluid
with
high
protein
concentration and cellular debris
o
high specific gravity-increased capillary
permeability
b.
Transudate
o
fluid with low protein content
o
low specific gravity
o
ultrafiltrate of blood plasma results from
osmotic or hydrostatic imbalance across the
vessel wall
Light criteria
pleural fluid/serum protein ration > 0.50
Pleural fluid/serum LD ration > 0.60
Pleural fluid LD >200 IU

Edema
denotes an excess of fluid in the interstitial tissue or serous
cavities
can be either an exudate or a transudate

Pus
a purulent exudate
rich in leukocytes (mostly neutrophils) and necrotic debris

Changes in Vascular Flow and Caliber

Vasodilation
o
earliest manifestation of acute inflammation
o
sometimes follows a transient constriction of
arterioles
o
first involves the arterioles and then leads to
opening of new capillary beds in the area

results in increased blood flow - cause of

erythema
o
induced by action of mediator on vascular smooth
muscle cells such as:
a.
Histamine
b.
Nitric Oxide
Increased Permeability of the microvasculature
o
immediately follows vasodilation
o
accompanied by outpouring of protein-rich fluid
into the extravascular tissue
Stasis
o
loss of fluid and increased vessel diameter leads to
a.
slower blood flow
b.
concentration of RBC in small vessels
c.
increased viscosity of the blood
o
results in dilation of small vessels that are packed
with slowly moving cells - STASIS (vascular
congestion)
Accumulation of leukocytes
o
principally neutrophils, accumulate along the
vascular endothelium.
o
endothelial cells are activated by mediators
produced at sites of infection, express increased
levels of adhesion molecules
o
leukocytes adhere to endothelium
o
leukocytes undergo migration through the vascular
wall into the interstitial tissue
Increased Vascular Permeability (Vascular leakage)
hallmark of acute inflammation: increased vascular
permeability leading to escape of protein rich exudate
into the extravascular tissue, causing edema
mechanisms involved for increased vascular permeability:
a.
Contraction of Endolethial cells results in increased
interendothelial spaces

most common mechanism of vascular leakage

elicited by
o
histamine
o
bradykinin
o
leukotriene
o
substance P
o
other chemical mediators

Immediate transient response - occurs rapidly after

exposure to the mediator; short lived (15-30 minutes)

Delayed prolonged leakage - begins after a delay of 2 to

12 hours, lasts for several hours; caused by contraction
of endothelial cells or endothelial damage
b. Endothelial injury , resulting in endothelial cell necrosis and
detachment

neutrophils that adhere to endothelium during

inflammation may injure endothelial cells amplify the
reaction
c.
Transcytosis

increased transport of fluids, through the endothelial

cells

Vesiculovacuolar organelle - involved in transcytosis;

channels that are consisted of interconnected,
uncoated
vesicles and vacuoles, located close to
intercellular junctions
Principal Mechanism of Increased Vascular Permeability in
Inflammation:

Normal

Retraction of Endothelial Cells

occurs mainly in venules

induced by histamine, NO and other mediators

rapid and short-lived

Endothelial Injury

occurs in arterioles, capillaries, venules

caused by burns, some microbial toxins

rapid; long lived

Leukocyte Mediated Vascular Injury

occurs in venules, pulmonary capillaries

associated with late stages of inflammation

long-lived

Increased Transcytosis

occurs in venules

induced by VEGF

Responses of Lymphatic Vessels

Inflammation: lymph flow
a.
is increased
b.
helps drain edema fluid that accumulates due to
increased vascular permeability
Leukocytes, cell debris
Lymphatic vessels proliferate during inflammatory reactions
to handle increased load:

Lymphangitis - secondarily inflamed

Lymphadenitis - draining lymph nodes

inflamed lymph nodes are often enlarged because of
a.
hyperplasia of the lymphoid follicles and
b.
increased number of lymphocytes and macrophages.

Reactive, Inflammatory Lymphadenitis - constellation of

pathologic changes
REACTIONS OF LEUKOCYTES IN INFLAMMATION
-

Neutrophils and Macrophage

most important leukocytes in inflammatory reaction

capable of phagocytosis

functions to
a.
ingest and kill bacteria and other microbes
b.
eliminate necrotic tissue and foreign substances
c.
produce growth factors that aid in repair
Leukocytes, when strongly activated, may induce tissue
damage and prolong inflammation (leukocyte products that
destroy microbes and necrotic tissues can also injure normal
host tissues
process involving leukocytes in inflammation consists of:
1.
recruitment from the blood into extravascular tissue
2.
recognition of microns and necrotic tissues
3.
removal of offending agent

Recruitment of Leukocytes to Sites of Infection and Injury

Extravasation

journey of leukocytes from vessel lumen to

interstitial tissue.

the

CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
1.

2.
3.

In the lumen (margination, rolling and adhesion to

endothelium)
vascular endothelium in its endothelium in its normal,
inactivated state does not bind leukocytes, as a prelude
to their exit from the blood vessels.
migration across the endothelium and vessel wall
migration in the tissues toward a chemotactic stimulus

Leukocyte Adhesion to Endothelium

normally flowing blood in venules:
a.
RBC are confined to the central axial column
b.
displacing the leukocytes towards the wall of
the vessel
because blood flow slows early in inflammation (stasis):
a.
hemodynamic condition changes (wall shear
stress decreases)
b.
more WBC assume a peripheral position
along the endothelial surface.
MARGINATION - process of leukocyte redistribution
ROLLING - Individual and then rows of leukocytes adhere
transiently to the endothelium, detach and bind again
ADHESION - cells finally come to rest at some point where
they adhere firmly.
o
adhesion of leukocytes to endothelial cells is
mediated by complementary adhesion molecules
on the two cell types.
Cytokines

secreted by cells in tissues in response to microbes

and other injurious agents

ensures leukocytes are recruited to the tissues

where the stimuli are present
Selectin

initial rolling interactions are mediated by selectins.

has 3 types
o
L- selectin - leukocytes
o
E - selectin - endothelium
o
P - selectin - platelets and on endothelium

ligands for selectin are sialylated oligosaccharides

bound to mucin-like glycoprotein backbone
Tissue macrophages, mast cells and endothelial cells that
encounter microbes and dead tissues respond by secreting
several cytokines including:
a.
TNF (tumor necrosis factor)
b.
IL-1 (interleukin-1)
c.
chemokines (chemoattractant cytokines)

TNF and IL-1 act on the endothelial cells of post

capillary venules adjacent to the infection and induce
the coordinate expression of numerous adhesion
molecules.
Within 1 to 2 hours, the endothelial cells begin to express Eselectin and the ligands for L-selectin.
other mediators such as HISTAMINE, THROMBIN, and
PLATELET-ACTIVATING FACTOR stimulate the redistribution of
P-selection from its normal intracellular stores in endothelial
cell granules (Weibel-Palade bodies) to cell surface.
Leukocytes:

express L selectin at the tips of their microvilli

also express for E and P selectins

all bind to the complementary molecules on the

endothelial cells

low affinity interactions with a fast off-rate

easily disrupted by the flowing blood.

results in the binding of leukocytes, detachment

and binding again, and this begin to roll along the
endothelial surface.
Weak rolling interaction slow down the leukocytes - give
opportunity to bind more firmly to the endothelium
INTEGRINS
o
mediates firm adhesion
o
family of heterodynamin leukocyte surface protein
Chemokines bind to endothelial cell proteoglycan
displayed at high concentrations on endothelial surface
Chemokines bind to and activate the rolling leukocytes

activation leads to conversion of VLA-4 and LFA-1

integrins on the leukocytes to a high affinity state

FIRM INTEGRIN MEDIATED BINDING OF LEUKOCYTES TO

THE ENDOTHELIUM AT THE SITE OF INFLAMATION IS
BROUGHT ABOUT BY:
a.
The combination of cytokine-induced expression of
integrin ligands on the endothelium
b.
activation of integrins on the leukocytes
Leukocyte stop rolling, cytoskeleton is reorganized and
spared out on endothelial surface.

Leukocyte Migration Through Endothelium

DIAPEDESIS
o
migration
of
leukocytes
through
the
endothelium
o
also known as transmigration
o
occurs mainly in post capillary venules
Several adhesion molecules present in the intercellular
junctions between the endothelial cells are involved in the
migration of leukocytes:
o
PECAM 1
o
junctional adhesion molecules
Genetic deficiencies in adhesion molecules

results in recurrent bacterial infections as a

consequence of impaired leukocyte adhesion and
defective inflammation
a.
Leukocyte Adhesion Deficiency type 1
o
defect in the biosynthesis of the beta-2
chain shared by LFA-1 and Mac-1
integrins
b.
Leukocyte Adhesion Deficiency type 2
o
caused by the absence of sialyl-Lewis X
(fucose containing ligand for P and E
selectins)
o
absence result of a defect in fucosyl
transferase (enzyme that attaches
fucose moieties to protein backbone)

Endothelial-Leukocyte Adhesion Molecules

Endothelial Molecule
Leukocyte Molecule
P selectin
Sialyl-Lewis-Xmodified proteins
E selectin
Sialyl-Lewis-Xmodified protiens
GlyCam-1, CD34
L selectin
ICAM-1
CD11,
CD
18,
integrins
VCAM - 1
VLA - 4

Major Role
Rolling
Rolling and Adhesion
Rolling
Adhesion,
Arrest,
transmigration
Adhesion

Chemotaxis of Leukocytes

Chemotaxis
o
leukocytes emigrate in tissues towards the site of
injury
o
locomotion originated along a chemical gradient
most
common
exogenous
agents
that
act
as
chemoattractant are bacteria products including:
a.
peptides that possess N-formylmethionine terminal
amino acid
b.
lipids
endogenous chemoattractant include:
a.
cytokines
b.
component of the complement system
c.
arachidonic acid metabolites
o
these chemotactic agents bind to specific seven
transmembrane G protein-coupled receptors on the
surface of leukocytes
o
signals from these receptors result in: activation of
2nd messengers that:

increase cytosolic Ca

activate small guanosine triphosphatase

of the Rac/Rho and cdc42 family ;
numerous kinase
o
signals induce polymerization of actin increased
amounts of polymerized actin at the leading edge
of the cell and localization of myosin filaments at
the back.
o
leukocytes migrate toward the inflammatory
stimulus in the direction of the gradient of locally
produced chemoattractant.

Neutrophils predominate in the inflammatory infiltrate

during the first 6 to 24 hours
o
early appearance of neutrophils is attributed
to
a.
they are numerous in the blood
b.
respond more rapidly

Monocyte replace neutrophils in the 24 to 48 hours

Pseudomonas bacteria - cellular infiltrate is dominated

by continuously recruited neutrophils for several days

Viral infections - lymphocytes may the first cells to

arrive

CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION

Hypersensitivity reactions - eosinophils are the main

cell types

Recognition of Microbes and Dead Tissues

Once leukocytes (neutrophils and monocytes) have been
recruited to the site of infection or necrosis, they must be
activated to perform their functions
responses of leukocytes consist of 2 sequential set of events:
1. recognition of offending agents (deliver signals that
2. activate the leukocytes to ingest and destroy offending
agents & amplify the inflammatory reaction.
Receptors that recognize external stimuli and deliver
activating signals expressed by leukocytes are:
a.
Receptors for microbial products: Toll-like receptors (TLRs)
o
play essential role in cellular responses to:
a.
bacterial lipopolysaccharide (LPS or endotoxin)
b. other bacterial proteoglycans and lipids
c.
unmethylated CpG nucleotides
all are abundant in bacteria
double stranded RNA (viruses)
o
present on cell surface and in the endosomal vesicle of
the leukocytes
o
TLRS function through receptor-associated kinase to
stimulate the production of microbicidal substances and
cytokines by leukocytes
b. G protein-coupled receptors
o
found on neutrophils, macrophages and most
other leukocytes
o
bacterial peptides containing N-formylmethionyl
residues
o
other G protein coupled receptors recognize:
a.
chemokines
- breakdown products of
complement such as c5a
b. lipid mediators

PAF

prostaglandins

leukotriene
o
binding of ligands to G protein-coupled receptors
induces
a.
migration of the cells from the blood through
the endothelium
b.
production of microbial substances by
activation of the respiratory burst
c.
Receptors for Opsonin
o
Opsonization - coating a particle to target for
ingestion.
o
substance for opsonization include:
a.
antibodies
b.
complement proteins
c.
lectins
o
Most efficient way: coating the particles with IgG
antibodies specific for particles

recognize by the Fc receptor of

phagocytosis.
o
protein C3 - potent opsonins; fragments binds to
microbes and phagocytes express a receptor
(type 1 complement receptor)
d.

Receptors for Opsonins

o
one of the most important of these cytokines is
interferon-

secreted by natural killer cells reacting

to microbes and by antigen activated T
lymphocytes during adaptive immune
responses.

major macrophage-activating cytokine

Removal of the Offending Agents

Leukocyte activation

results in the increases in cytosolic Ca and activation of

enzymes such as protein kinase and phospholipase A2

The functional responses that are most important for

destruction of microbes and other offenders are
1.
phagocytosis and
2.
intracellular killing

Phagocytosis

involves 3 sequential steps:

1.
recognition and attachment of the particke to be
ingested by leukocyte
2.
engulfment -> phagocytic vacuole
3.
killing or degradation

Bind and ingest microbes:

a.
mannose receptors
b.
scavenger receptrs
c.
receptors for various opsonins
Macrophage mannose receptor - function to bind and
ingest microbes
o
lectin
o
binds terminal mannose and fucose residues
Scavenger receptors

Engulfment

pseudopods

plasma membrane pinches off to form a phagosome

that encloses the particle

phagosome fuses with a lysosomal granule discharge

of the granules content/

phagocyte may also release granule contents into the

extracellular space

Killing and Degradation

final step; killing and degradation within neutrophils

and macrophages

occur most efficiently after activation of the phagocytes

microbial killing is accomplished largely by

a.
ROS
b.
reactive nitrogen species derived from NO

Respiratory burst - neutrophils; rapid oxidative reaction

is triggerd by activating signals and accompanies
phagocytosis

the H202-MO-Halide system is the most efficient

bactericidal system of neutrophils

Other Functional Responses of Activated Leukocytes

production of GF that
a.
stimulate the proliferation of endothelial cells and
fibroblast
b.
synthesis of collagen and enzymes that remodel tissue
Release of Leukocyte Produts and Leukocyte Mediated Tissue
Injury
Leukocytes are important causes of injury to normal cells
and tissues under several cirumstances:
a.
normal defense reaction

adjacent tissue suffer collateral damage

TB, certain viral disease

prolonged host response contributes to the pathology

b.
When inflammatory response is unapproriately directed
against host tissue

autoimmune disease
c.
Host
reacts
excessively
against
usually
harmless
environmental substance

allergy, asthma
-

Lysosomal enzymes and Reactive oxygen and nitrogen

species: capable of damaging normal cells and vascular
endothelium amplify the effects of initial injurious agent.
Frustrated phagocytosis: inability of the leukocytes to
surround and ingest substances

Defects in Leukocyte Function

Inherited defects in leukocyte adhesion

Inherited defects in phagolysosome function

inherited defects in microbicidal activity

acquired deficiencies
- Cell residents in tissues: MAST CELLS and TISSUE MACROPHAGE

sentinel cells are stationed in tissues to rapidly

recognize potentially injurious stimuli ; initiate the host
defense reaction

TERMINATION OF ACUTE INFLAMMATORY RESPONSE

Inflammation
declines
because
the
mediators
of
inflammation are produced in rapid bursts.
As inflammation develops the process also triggers a variety
of stop signals that serves to actively terminate the reaction

switch in the type of AA metabolite produced - from

proinflammatory Leukotrienes to anti-inflammatory
lipoxins

liberation of anti inflammatory cytokines (TGF-b and IL10)

CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION

production of anti inflammatory lipid mediators resolvins and protectins

MEDIATORS OF INFLAMMATION

Mediators are generated either from cells or from

plasma proteins
Active mediators are produced in response to various
stimuli.
One mediator can stimulate the release of other
mediators
Mediators vary in their range of cellular targets
Once activated and released from cells, most of these
mediators are short lived.

CELL-DERIVED MEDIATORS
1.
-

VASOACTIVE AMINES: HISTAMINE AND SEROTONIN

have important actions on blood vessels
stored as preformed molecules in cells
first mediators to be released during inflammation

A.

Histamine
o
richest source of histamine are mast cells that are
normally present in the connective tissue adjacent
to blood vessels
o
also found in blood basophils and platelets
o
present in mast cell granules and is released by
mast cell degranulation in response to a variety of
stimuli including:
a.
physical injury
b.
binding of antibodies to mast cells
c.
fragments
of
complement
called
anaphylatoxins (C3a and C5a)
d.
histamine releasing proteins derived from
leukocytes
e.
neuropeptides
f.
cytokines
o
causes dilation of arterioles and increases the
permeability of venules
o
considered to be the principal mediator of the
immediate transient phase of increased vascular
permeability
Serotonin
o
5-hydroxytryptamine
o
present in platelets and neuroendocrine cells
o
release from platelets is stimulated when platelets
aggregate after contact with:
a.
thrombin
b.
collagen
c.
ADP
d.
antigen-antibody complex
o
platelet release reaction (key component of
coagulation) results in increased vascular
permeability

2.
-

ARACHIDONIC ACID METABOLITES: PROSTAGLANDINS,

LEUKOTRIENE AND LIPOXINS
Prostaglandins and Leukotrienes
biologically active lipid mediators
Arachidonic Acid
o
20 carbon PUFA (5,8,11,14-eicosatetraenoic acid)
o
derived from dietary sources or from the EFA,
linoleic acid
o
does not occur in free cell
o
normally esterified in membrane phospholipid
AA derived mediators (aka EICOSANOIDS) are synthesized by
2 major classes of enzymes:

Cyclooxygenase - generate prostaglandin

Lipooxygenase - produce:

Leukotrienes

lipoxins

Cyclooxygenase
A.
Prostaglandins
o
produced by mast cells , macrophages, endothelial
cells and many other cell types
o
involved in the vascular and systemic reaction of
inflammation.
o
produced by the action of 2 cyclooxygenase:
a.
COX 1

b.
COX 2
most important PGs in inflammation are:
a.
PGE2
b.
PGD2
c.
PGF2
d.
PGI (prostacyclin)
e.
TXA2 (thromboxane)

TXA2 ( Thromboxane)

major end product of platelets that contain the enzyme

thromboxane synthetase

potent platelet aggregating agent and vasoconstrictor

unstable and rapidly converted to the inactive form

TXB2

PGI2 (Prostacyclin)

vascular endothelium

prostacyclin synthetase - formation of PGI2

vasodilator

potent inhibitor of platelet aggregation

potentiates
the
permeability
increasing
and
chemotactic effects of other mediators

PGD2

major prostaglandin made by mast cells

along with PGE2, it causes

a.
vasodilation
b.
increased permeability of post capillary venules
c.
potentiating edema formation

chemoattractant for neutrophils

PGF2a

stimulates the concentration of uterine and bronchial

smooth muscles and small arterioles

PGE2

hyperalgesic

makes the skin hypersensitive to painful stimuli

involve cytokine-induced fever during infections

o
prostaglandins are also involved in pathogenesis
of pain and fever
Lipooxygenase - enzymes responsible for production of:
A.
Leukotrienes
o
Secreted mainly by leukocytes
o
chemoattractant for leukocytes
o
have vascular effects
there are 3 different Lipooxygenase
5-lipooxygenase

is the predominant in neutrophils

converts
AA
to
5-hydroxyeicosatetraenoic
acid
(chemotactic
for
neutrophils;
precursor
for
Leukotrienes)
Leukotrienes are more potent than histamine in increasing
vascular permeability and causing bronchospasm

LTB4

potent chemotactic agent and activator of neutrophils

causing
a.
aggregation and adhesion of the cells to venules
endothelium
b.
generation of ROS
c.
release of lysosomal enzymes

CD4,D4 and E4 (cysteinyl-containing Leukotrienes)

cause intense vasoconstriction

bronchospasm

increased vascular permeability

vascular leakage is restricted to venules

o

B.

Lipoxins
o
o
o

o
o

generated from AA by the Lipooxygenase pathway

inhibitors of inflammation
requires 2 cell population for transcellular
biosynthesis

Neutrophils produce intermediates in

lipoxins synthesis converted to
lipoxins by platelets interacting with
neutrophils
The principal actions of lipoxins are to inhibit
leukocyte recruitment and the cellular components
of inflammation
inverse relation between the production of lipoxins
and Leukotrienes

lipoxins may be endogenous negative

regulators of Leukotrienes play a role
in resolution of inflammation
ANTI INFLAMMATORY DRUGS

CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
-

work by inhibiting the synthesis of eicosanoids

Cyclooxygenase inhibitors
o
aspirin, NSAIDS
o
inhibit both COX 1 and COX 2 inhibit
prostaglandin synthesis
Lipooxygenase inhibitor
o
5-lipooxygenase is not inhibited by NSAIDS
o
leukotriene production; block leukotriene receptors
Broad spectrum inhibitors (i.e. corticosteroids)
o
act by reducing the transcription genes encoding
COX-2,
phospholipase
A2,
proinflammatory
cytokines and iNOS

Fish oil
o
o

3.

4.
-

5.
-

6.
-

Tumor

Polyunsaturated fatty acids in fish oil serve as poor

substrate for conversion to active metabolites by
both cyclooxygenase and Lipooxygenase pathways
excellent substrates for the production of antiinflammatory lipid products called resolvins and
protectins.

PLATELET ACTIVATING FACTOR

o
phospholipid derived mediator
o
variety of cell types:

platelets

basophils

mast cells

neutrophils

macrophages

endothelial cells
o
platelet aggregation
o
causes vasoconstriction and bronchoconstriction
o
at extremely low concentrations, it induces
vasodilation and increased venular permeability
with a potency 100 to 10000 times greater than
that of histamine.
o
also causes
a.
increased leukocyte adhesion to endothelial
cells
b.
Chemotaxis
c.
degranulation
d.
oxidative burst
o
can elicit most of the vascular and cellular
reactions of inflammation
o
boost synthesis of other mediators
REACTIVE OXYGEN SPECIES
endothelial cell damage with resultant increased vascular
permeability
injury to other cell types
inactivation of proteases
antioxidants include
1. superoxide dismutase
2. catalase
3. glutathione peroxidase
4. ceruloplasmin
5. iron free fraction of serum transferrin
NITRIC OXIDE
synthesized from L-arginine by the enzyme nitric oxide
synthase.
has dual actions in inflammation:
1. it relaxes vascular smooth muscle and promotes
vasodilation contributing to the vascular reaction
2. also an inhibitor of the cellular component of the
inflammatory response
NO also
a.
reduces platelet aggregation and adhesion
b. inhibits several features of mast cell-induced
inflammation and
c.
inhibits leukocyte recruitment.

inhibitory actions: production of NO is thought to be an

endogenous mechanism for controlling inflammatory
responses
CYTOKINES AND CHEMOKINES
Cytokines

proteins produced principally by activated

lymphocytes and macrophages
o
also produced by endothelial, epithelial and
connective tissue cells
o
modulate the function of other cell types
Necrosis Factor and Interleukin-1
TNF and IL-1 are the major cytokines that mediate
inflammation
produced mainly by activated macrophages
secretion can be stimulated by endotoxin, and other
microbial products, immune complex, physical injury and a
variety of inflammatory stimuli
most important action on inflammation
a.
effects on endothelium, leukocytes, and fibroblasts

induce endothelial activation:

expression of endothelial adhesion molecules

induce synthesis of chemical mediators

production of enzymes
associated with
matrix remodeling

increases in the surface thrombogenicity of

the endothelium
b.
induction of systemic acute phase reaction
o

TNF augments responses of neutrophils to other stimuli such

as bacterial endotoxin
Production of IL-1 is controlled by inflammasome

Inflammasome

multi protein complex

response to stimuli from microbes and dead

cells

activates protease that are members of the

caspase family

function to cleave the newly synthesized

inactive precursors of IL-1 into biologically
active cytokines

mutations in genes encoding inflammasome

are the cause of inherited auto inflammatory
syndrome (familial Mediterranean fever)
Autoinflammatory syndrome

mechanism:
a.
constitutively activate the inflammatory caspase
b.
interfere with negative regulation

net result is unregulated IL-1 production

px have fever and other systemic manifestation of

inflammation without overt provocation

Amyloidosis - extracellular protein deposition; result of

persistent inflammation
Chemokines
o
family of small proteins that act primarily as
chemoattractant for specific types of leukocytes
o
four major groups are classified according to the
arrangement of conserved cysteine (C) residues in
mature protein
C-X-C chemokines
o
also called a chemokines
o
one amino acid residue separating the first two
conserved cysteine residues
o
act primarily on neutrophils
o
IL-8 is typical
o
secreted by activated macrophages, endothelial
cells and other cell types
o
causes activation and Chemotaxis of neutrophils
o
most important inducers are microbial products
and cytokines (IL-1 and TNF)
C-C Chemokines
o
also called chemokines
o
first 2 conserved cysteine residues adjacent
o
include
monocyte
chemoattractant
protein,
eotaxin, macrophage inflammatory protein and
RANTES generally attract monocytes, eosinophils,
basophils and lymphocytes but not neutrophils.
o
Eotaxin selectively recruit eosinophils
C chemokines
o
chemokines
o
lack two (1st and 3rd) of the four conserved
cysteines
o
relatively specific for lymphocytes
CX3C chemokines
o
contains 3 amino acids between 2 cysteines

CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
o

fractalkine

exist in 2 forms:
1.
cell surface bound protein can be induced on
endothelial cells by inflammatory cytokines promotes strong adhesion of monocyte and Tcell
2.
soluble form

chemokines have 2 main function

a.
stimulate leukocyte recruitment in inflammation
b.
control the normal migration of cells through various
tissues
-

Other Cytokines
A.
IL-6

made by macrophages and other cells

involved in local and systemic reactions

B.
IL-7

produced mainly by T-lymphocytes

promotes neutrophil recruitment

7.
-

8.
-

LYSOSOMAL CONSTITUENTS OF LEUKOCYTES

neutrophils and monocytes contain lysosomal granules
which, when released may contribute to the inflammatory
response
Neutrophils have 2 main type of granules:
a.
smaller specific granules

contain:
o
lysozyme
o
collagenase
o
gelatinase
o
lactoferrin
o
plasminogen activator
o
histaminase
o
alkaline phosphatase
b. larger azurophil granules

contain
o
myeloperoxidase
o
bacetiricidal factors
o
acid hydrolase
o
neutral protease
both types can fuse with phagocytic vacuoles
Acid protease

degrade bacteria and debris within the phagolysosomes

in which an acid pH is achieved
Neutral protease

capable of degrading various extracellular components

such as collagen, basement membrane, fibrin, elastin
and cartilage

results in tissue destruction

can also cleave C3 and C5

releasing anaphylatoxins and kininogen (kinin-like

peptide)
NEUROPEPTIDES
Neuropeptides are secreted by the sensory nerves
play a role in the initiation and propagation
inflammatory response
Substance P and neurokinin A
Substance P

prominent in lungs and GI tract

functions for
a.
transmission of pain signals
b. regulation of blood pressure
c.
stimulation of secretion by endocrine cells
d. increasing vascular permeability

of

an

PLASMA PROTEIN-DERIVED MEDIATORS

Complement System
consists of more than 20 proteins, some of which are
numbered C1 through C9
function both innate and adaptive immunity for defense
against microbial pathogens
Complement proteins are present in inactive forms in the
plasma; many are activated to become proteolytic enzymes
that degrade other proteins cascade
critical step in complement: proteolysis of the third
component, C3

cleavage of C3 can occur by one of the three pathways:

1.
classic pathway

triggered by the fixation of C1 to

antibody (IgG or IgM) that has combined
with an antigen
2.
alternative pathway
o
can be triggered by microbial surface
molecules,
complex
polysaccharide,
cobra venom and other substances in
the absence of an antibody
3.
lectin pathway
o
plasma mannose -binding lectin binds to
carbohydrates on microbes and directly
activates C1
all pathways led to the formation of an active enzyme, C3
convertase

enzyme splits C3 into C3a and C3b; C3a is released and

C3b becomes attached to the cell or molecule where
complement is being activated.
More C3b binds to previously generated fragment form C5
convertase

C5 convertase cleaves C5 to release C5 a and leave C5

b attached to the cell surface

C5b binds to late components (C6-C9) formation of

the membrane attack complex
function of the complement system includes:
1.
inflammation

C3a, C5a and C4a - cleavage products of the

corresponding complement components stimulate
histamine release from mast cells increase vascular
permeability and cause vasodilation

anaphylatoxins

C5a
o
powerful chemotactic agent for neutrophils,
monocytes, eosinophils and basophils
o
activates lipooxygenase pathway of AA metabolism
further release of inflammatory mediators
2.
phagocytosis

C3b and its cleavage iC3b, when fixed to a microbial

cell wall act as opsonins and promote phagocytosis
by neutrophils and macrophages
3.
cell lysis

deposition of MAC makes cell permeable to water

and ions lysis of cells
o

C3a and C5a re the most important inflammatory mediators

in the complement system

C3 and C4 can be cleaved by several proteolytic

enzymes present within the exudate

activation is tightly controlled by cell associated and

circulating regulatory proteins
Coagulation and Kinin System

inflammation and blood clotting are often intertwined

clotting system is divided into two pathways that converge,
culminating in the
a.
activation of thrombin and
b.
the formation of fibrin
intrinsic clotting pathway

activated by Hageman factor (XII) ; synthesized by the

liver; circulates in an inactive form

Factor XII activated upon contact with negatively

charged surfaces and come in contact with collagen
undergoes conformation change becomes factor XIIa,
exposing a serine center that subsequently cleave
protein substrates and activate mediator systems
Thrombin (product of clotting) promotes inflammation by
engaging Protease-Activated Receptors

engagement to PAR -1 by thrombin triggers several

responses that induce inflammation; includes:
a.
mobilization of P selectin
b.
production of chemokines and other cytokines
c.
expression of endothelial adhesion molecules for
integrins
d.
induction of COX2 and production of prostaglandins
e.
production of PAF and NO
f.
changes in endothelial shape
-

Kinins

are vasoactive peptides derived from plasma protein

called kininogen by the proteases kallikreins
Factor XIIa converts plasma prekallikrein to kallikrein
cleaves plasma protein glycoprotein precursor, HMWK
produce bradykinin.
Bradykinin

increases vascular permeability

CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION

causes contraction of smooth muscles

dilation of blood vessels
pain
short lived action; quickly inactivated by kininase

Kallikrein

potent activator of Hageman factor

allowing for autocatalytic amplification of the initial

stimulus.

converts C5 to C5a
Factor XIIa

simultaneously induces fibrin clot formation and

activates fibrinolytic system
o
cascade counterbalances clotting by clearing
fibrin, solubilizing the clot.

Note that:

Most important in vivo are

a.
Bradykinin, C3a and C5a (mediators of increased
vascular permeability)
b.
C5a (mediator of Chemotaxis)
c.
thrombin (effects on endothelial cells and many other
cell types)

C3a and C5a can be generated by several types of reaction:

1.
immunologic reactions, involving antibodies and
complement (classical pathway)
2.
activation of the alternative and lectin complement
pathways by microbes in the absence of antibodies
3.
agents not directly related to immune response
(plasmin, kallikrein and serine protease) found in
normal tissue

Activated Hageman Factor initiates four system involved in

the inflammatory response
1.
kinin system - produces vasoactive kinin
2.
clotting system - induces formation of thrombin, which
has inflammatory properties
3.
fibrinolytic system - produces plasmin and degrades
fibrin to produce fibrinopeptides, which induce
inflammation
4.
complement system - produces anaphylatoxins and
other mediators
OUTCOMES OF INFLAMMATION
1.

2.

3.

all acute inflammatory reactions have one of the three

outcomes:
Complete Resolution

Resolution
o
restoration of the site of acute inflammation
to normal
o
usual outcome when:
a.
the injury is short lived
b.
there has been little tissue destruction and
the
damaged
parenchymal
cells
can
regenerate.

involves removal of the cellular debris and microbes by

macrophages

also involves the resorption of edema fluid by

lymphatics

also:
a.
clearance of injurious stimuli
b.
clearance of mediators and acute inflammatory
cells
c.
replacement of injured cells
d.
normal function
Healing by a connective tissue replacement (Fibrosis)

occurs after substantial tissue destruction

o
tissue destruction happens when:
a.
the inflammatory injury involves tissues
that are incapable of regeneration
b.
there is abundant fibrin exudation in
tissues or serous cavities that cannot be
cleared

connective tissue grown into the area of damage or

exudate, converting into a mass of fibrous tissue
(ORGANIZATION)

collagen deposition

loss of function
Progression of the response to chronic inflammation

may follow acute inflammation or the response may be

chronic from the onset
occurs when acute inflammatory response cannot be
resolved as a result of
a.
the persistence of the injurious agent
b.
interference with the normal process of healing
chronic inflammation comprises
a.
angiogenesis
b.
mononuclear cell infiltrate
c.
fibrosis (scar)
d.
progressive tissue injury

MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION

-

morphologic hallmarks of all acute inflammatory

reaction are:
1.
dilation of small blood vessels
2.
slowing of blood flow
3.
accumulation of leukocytes and fluid in the
extravascular tissue
special morphologic patterns are often superimposed

SEROUS INFLAMMATION
-

marked by the outpouring of a thin fluid that may be derived

from
a.
plasma
b.
secretion of mesothelium cells lining the peritoneal,
pleural and pericardial cavities
Effusion: accumulation of fluid in cavities

FIBRINOUS INFLAMMATION
greater increase in vascular permeability large molecules
(i.e. fibrinogen) pass the vascular barrier, and fibrin is
formed and deposited in extracellular spaces.
Fibrinous exudate develops:
a.
when vascular leaks are large
b.
there is a local procoagulant stimulus
Fibrinous exudate is characteristic of inflammation in the
lining of body cavities, such as the meninges, pericardium
and pleura.
Fibrin appears as:

eosinophilic meshwork of threads

sometimes as an amorphous coagulum.

Fibrinous exudates may be removed by fibrinolysis and
clearing of other debris by macrophages
Scarring

fibrin is not removed

stimulate the ingrowth of fibroblasts and blood vessels

Organization: conversion of the fibrinous exudates to scar
tissue within the pericardial sac leads to opaque fibrosis of
the pericardium and epicardium
Extensive fibrosis leads to obliteration of the pericardial
space
SUPPURATIVE or PURULENT INFLAMATION; ABSCESSES
-

ULCERS

characterized by the production of large amount of pus or

purulent exudate that consists of:

neutrophils

liquefactive necrosis

edema fluid
acute appendicitis
staphylococci
Abscesses

are localized collections of purulent inflammatory tissue

caused by suppuration buried in a tissue, organ or
confined space

produced by deep seeding of pyogenic bacteria into a

tissue

Abscesses have

a central region that appears as a mass of

necrotic leukocytes and tissue cells

zone of preserved neutrophils around the

necrotic focus

outside
is
a
vascular
dilation
and
parenchymal and fibroblastic proliferation
(indicating chronic inflammation)
abscess may be walled off and replaced by connective tissue

CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
-

Ulcer

local defect or excavation of the surface of an organ or

tissue

produced by the sloughing of inflamed necrotic tissue

Ulceration occur only when tissue necrosis and resultant
inflammation exist on or near a surface.
commonly encountered in:
1.
mucosa of the mouth, stomach, intestine or
genitourinary tract
2.
skin and subcutaneous tissue of the lower extremities in
older persons
Ulceration are best exemplified by peptic ulcer of stomach or
duodenum, which are acute and chronic inflammation
coexist

acute stage - intense polymorphonuclear infiltration

and vascular dilation in the margins of defect

chronic - the margins and base of the ulcer develop

fibroblastic proliferation, scarring and the accumulation
of lymphocyte, macrophage and plasma cells

CHRONIC INFLAMMATION
-

inflammation of prolonged duration (weeks/months)

inflammation, tissue injury and attempts at repair coexist in
varying combinations.
It may follow acute inflammation
may begin insidiously, as a low grade, smoldering response
without any manifestations of an acute reaction.

cause of tissue damage

rheumatoid arthritis, atherosclerosis, tuberculosis and

pulmonary fibrosis

implicated in cancer

CAUSES OF CHRONIC INFLAMMATION

1.
Persistent infections
microorganisms that are difficult to eradicate such as
mycobacteria, viruses and fungi as well as parasites
the organisms evoke an immune reaction called delayedtype hypersensitivity
inflammatory response takes a pattern called granulomatous
reaction
2.
-

Immune mediated inflammatory disease

Autoimmune diseases

autoantigens evoke a self perpetuating immune

reaction that results in chronic tissue damage and
inflammation
multiple sclerosis; rheumatoid arthritis
inflammatory bowel disease -> result of unregulated
immune response against microbes
Fibrosis may dominate the late stages

3.
-

Prolonged exposure to potentially toxic agents

silica SILICOSIS (inflammatory lung disease)

MORPHOLOGIC FEATURES
note that in acute inflammation, manifestation of AI include:
1.
vascular changes
2.
edema
3.
neutrophil infilitration
chronic inflammation is characterized by:
a.
infiltration with mononuclear cells
b.
tissue destruction induced by the persistent offending agent
or by the inflammatory cells
c.
attempts at healing by connective tissue replacement of
damaged tissue accomplished by angiogenesis and
fibrosis
ROLE OF MACROPHAGES IN CHRONIC INFLAMMATION
Macrophage

dominant cellular player in chronic inflammation

one component of the mononuclear phagocyte system

monocytes begin to emigrate into the extravascular tissues
early in the in the acute inflammation
within 48 hours: constitute the predominant cell type
Extravasation of monocyte is governed by adhesion moleculs
and chemical mediators with chemotactic and activating
properties
When monocyte reachers the extravascular tissue
undergoes transformation into larger, phagocytic cell ,
MACROPHAGE.
the products of activated macrophage serve to eliminate
injurious agents such as microbes and to initiate the process

of repair; responsible for much of the tissue injury in chronic

inflammation
tissue destruction is of the hallmarks of chronic
inflammation.

OTHER CELLS IN CHRONIC INFLAMMATION

Lymphocytes
o
nteract with macrophage in a bidirectional way
o
immune inflammation

inflammation with a stron component of immune

reactions
Plasma cells
o
develop from activated B lymphocytes
o
produce antibodies directed either against persistent foreign
or self antigens in the inflammatory site or against altered
tissue components.
o
lymphoid organogenesis

chronic inflammatory disease i.e. RA

accumulation of lymphocyte, APC and plasma cells

assume the morphologic features of a lymphoid organ.
Eosinophils
o
IgE and in parasitic infections
o
eotaxin - chemokine impt for eosinophil recruitment.
o
Eosinophils have granules that contain major basic protein
Mast Cells
o
widely distributed in connective tissues
o
participate in both acute and chronic inflammation
o
IgE antibody
GRANULOMATOUS INFLAMMATION
Granulomatous inflammation

distinctive pattern of chronic inflammation

Granuloma

cellular attempt to contain an offending agent that is difficult

to eradicate.

strong activation of T lymphocytes macrophage activation

injury to normal tissues
A granuloma is a focus of chronic inflammation consisting of
a microscopic aggregation of macrophages that are
transforemed into epithelium-like cells, surrounded by a
collar of mononuclear leukocytes (lymphocytes) and plasma
cells.
Epitheliod cells have pale pink granular cytoplasm with
indistinct cell boudnaries
two types of granulomas:
1.
Foreign body granulomas
2.
Immune granulomas

SYSTEMIC EFFECTS OF INFLAMMATION

-

A.

Acute phase response

systemic changes associated with acute inflammation

systemic inflammatory response syndrome

Changes are reactions to cytokines whose production is
stimulated by
a.
bacterial products such as LPS
b.
other inflammatory stimuli
clinical and pathological changes are:
FEVER
o

elevation of body temperature by usually 1 to 4C

most prominent manifestations of acute phase
response
o
esp. when inflammation is associated with
infection
o
produced in response to substances
called
pyrogens that act by stimulating prostaglandin
synthesis in the vascular and perivascular cells of
the hypothalamus.
Mechanism:
a.
bacterial products such as LPS stimulate leukocytes to
release cytokines such as IL-1 and TNF that increase
the enzymes that convert AA into prostaglandins
b.
in the hypothalamus, the prostaglandins, especially
PGE2, stimulate the production of neurotransmitters
such as CAMP (function to reset the temperature set
point at higher level)
Fever may induce heat shock proteins that enhance
lymphocyte response to microbial antigens

CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
B.
-

C.
-

D.

ACUTE PHASE PROTEINS

Acute Phase proteins
o
plasma proteins
o
mostly synthesized in the liver;
plasma
concentrations may increase several hundred-fold
as part of the response to inflammatory stimuli
o
Three of the best-known of these proteins are
1.
C-reactive protein (CRP)
2.
fibrinogen
3.
serum amyloid A (SAA) protein
LEUKOCYTOSIS
a common feature of inflammatory reactions, especially
those induced by bacterial infections
Leukemoid reactions
o
extreme elevations
o
15,000 or 2000 cells/uL; reach extraordinarily high
levels of 40k to 100k
OTHER MANIFESTATIONS INCLUDE
1. increase pulse and blood pressure
2. decreased sweating - because of redirection of blood
flow from cutaneous to deep vascular beds
3. rigors

E.
-

4. chills
5. anorexia
6. somnolence
7. malaise
SEPSIS
large amounts of organisms and LPS in the blood stimulate
the production of enormous quantities of several cytokines ,
TNF and IL-1
septic shock

CONSEQUENCES OF DEFECTIVE OR EXCESSIVE INFLAMMATION

A.
B.
-

DEFECTIVE INFLAMMATION
results in increased susceptibility to infection
associated with delayed wound healing
EXCESSIVE INFLAMMATION
Allergies
artherosclerosis
ischemic heart disease
Alzheimers disease

10