Acute and chronic inflammation

Dr. Wasan K.Darwish

 Inflammation
A protective response involving host cells, blood vessels and
proteins.
Goals are:
• eliminate the initial cause of cell injury
• Remove necrotic cells and tissue
• Initiate the process of repair

Also a potentially harmful process:

• Components of inflammation that are capable of destroying
microbes can also injure bystander normal tissue.
 Inflammation
• Components of the inflammatory process include white blood
cells and plasma proteins:
 Normally present in the blood
 The inflammatory reaction’s goal is to bring these to the site
of infection and/or tissue damage

• inflammation is induced by chemical mediators produced by :

 Damaged host cells
 Cytokines and other mediators

• Inflammation is normally controlled and self-limited .

Excess • Inappropriate inflammatory
inflammatory response when there are no
reactions foreign substances to fight
off leads to autoimmunity.

• Inflammatory process must

be tightly regulated by the
immune system to avoid
excessive tissue damage and
spillover to normal tissue.
 Cardinal signs of inflammation
• Heat (calor)
• Redness (rubor)
• Swelling (tumor)
• Pain (dolor)
• Loss of function
Components of acute and chronic
inflammation
Acute V.S Chronic inflammation
 Acute inflammation
Stimuli for Acute Inflammation :

 Infections (bacterial, viral, fungal, parasitic) & microbial toxins

 Tissue necrosis: ischemia, trauma, physical or chemical injury

(e.g., thermal injury; irradiation; some environmental
chemicals)

 Foreign bodies (splinters, dirt, sutures)

 Immune reactions (also called hypersensitivity reactions)

Acute
Main components:
inflammation
Vascular changes:
o Vasodilation.
o Vascular permeability.
o Increased adhesion of white
blood cells.

 Cellular events
o Cellular recruitment and
activation of neutrophils
(polymorphonuclear
leukocytes).
 Acute Inflammation
1. Vasodilation:
Alterations in vascular caliber (diameter) :
- Causes decrease in blood pressure

2. Vascular leakage and edema:

- The accumulation of fluid and proteins of plasma in the extravascular
tissues (interstitium)

3. Leukocyte emigration to extravascular tissues:

A. Margination and rolling
B. Activation and adhesion
C. Transmigration
 1. Vasodilation
 Vasodilation is one of the earliest manifestations of acute
inflammation; sometimes it follows a transient constriction of
arterioles, lasting a few seconds.

 Vasodilation first involves the arterioles and then leads to opening

of new capillary beds in the area. The result is increased blood
flow, which is the cause of heat and redness (erythema) at the site
of inflammation.

 Vasodilation is induced by the action of several mediators, notably

histamine and nitric oxide (NO), on vascular smooth muscle.
 Vasodilation

• Vasodilation is quickly followed by increased permeability of

the microvasculature, with the outpouring of protein-rich fluid
into the extravascular tissues

• The loss of fluid and increased vessel diameter lead to slower

blood flow, concentration of red cells in small vessels, and
increased viscosity of the blood.

• These changes result in dilation of small vessels that are

packed with slowly moving red cells, a condition termed stasis,
which is seen as vascular congestion (producing localized
redness) upon examination of the involved tissue.
 Vasodilation
• As stasis develops, blood leukocytes, principally neutrophils,
accumulate along the vascular endothelium.

• At the same time endothelial cells are activated by mediators

produced at sites of infection and tissue damage, and express
increased levels of adhesion molecules.

• Leukocytes then adhere to the endothelium, and soon afterward

they migrate through the vascular wall into the interstitial tissue.
 2. Vascular leakage and edema

• Outpouring of protein-rich fluid (exudate) into

the extracellular tissues leads to:
 Reduction of intravascular osmotic pressure
 Increase in extravascular/interstitial osmotic
pressure

• Increase of interstitial osmotic pressure leads to

edema (water and ions)
 mechanisms of increased vascular permeability
A. Contraction of endothelial cells resulting in increased interendothelial
spaces:
 Histamines, bradykinins, leukotrienes, the neuropeptide substance P

B. Endothelial injury resulting in endothelial cell necrosis and

detachment.
 encountered in severe injuries, for example, in burns, or by the actions of
microbes that target endothelial cells.
 Neutrophils that adhere to the endothelium during inflammation may
also injure the endothelial cells and thus amplify the reaction.
 In most instances leakage starts immediately after injury and is sustained
for several hours until the damaged vessels are thrombosed or repaired.

C. transcytosis: Increased transport of fluids and proteins through the

endothelial cell. This process may involve channels consisting of
interconnected, uncoated vesicles and vacuoles called the
vesiculovacuolar organelle.
 mechanisms of increased vascular
permeability

• Although these mechanisms of increased vascular permeability

are described separately, all probably contribute in varying
degrees in responses to most stimuli.

• The vascular leakage induced by all these mechanisms can

cause life-threatening loss of fluid in severely burned patients.
 REACTIONS OF BLOOD VESSELS
IN ACUTE INFLAMMATION

• In inflammation, blood vessels undergo a series of changes

that are designed to maximize the movement of plasma
proteins and circulating cells out of the circulation and into
the site of infection or injury.

• The escape of fluid, proteins, and blood cells from the

vascular system into the interstitial tissue or body cavities is
known as exudation.
 Exudate

Is an extravascular fluid that has a high protein concentration,

contains cellular debris, and has a high specific gravity.
Its presence implies an increase in the normal permeability of
small blood vessels in an area of injury and, therefore, an
inflammatory reaction .
 Exudate V.S Transudate
 Transudate : a fluid with low protein content (most of which is
albumin), little or no cellular material, and low specific gravity.
 an ultrafiltrate of blood plasma that results from osmotic or
hydrostatic imbalance across the vessel wall without an
increase in vascular permeability .
 Formation of
transudates and
exudates
A. the mean colloid osmotic
pressure of tissues is
approximately 25 mm Hg
(green arrows), which is equal to
the mean capillary pressure. the
net flow of fluid across the
vascular bed is almost nil.

B. A transudate is formed when

fluid leaks out because of
increased hydrostatic pressure or
decreased osmotic pressure.

C. an exudate is formed in
inflammation, because vascular
permeability increases as a result
of increased interendothelial
spaces.
 Definitions
• Edema denotes an excess of fluid in the interstitial
tissue or serous cavities; it can be either an exudate
or a transudate.

• Pus : is a purulent exudate, rich in leukocytes

(mostly neutrophils), the debris of dead cells and, in
many cases, microbes.
 Responses of Lymphatic Vessels
 The system of lymphatics and lymph nodes filters and polices the
extravascular fluids.

 lymphatics normally drain the small amount of extravascular fluid

that has seeped out of capillaries

 In inflammation, lymph flow is increased and helps drain edema

fluid that accumulates due to increased vascular permeability
 fluid, leukocytes, cell debris and microbes, may find their way into
lymph
 Lymphatic vessels, like blood vessels, proliferate during
inflammatory reactions to handle the increased load.
• The lymphatics may become secondarily inflamed
(lymphangitis), as may the draining lymph nodes
(lymphadenitis).

• Inflammatory/reactive lymphadenitis: Inflamed lymph nodes

are enlarged because of hyperplasia of the lymphoid follicles
and increased numbers of lymphocytes and macrophages.

• Lymphangitis: the presence of red streaks near a skin wound

is a telltale sign of an infection in the wound. This streaking
follows the course of the lymphatic channels.
 Leukocytes emigration to extravascular tissues
• The journey of leukocytes from the vessel lumen to the interstitial tissue,
called extravasation, can be divided into the following steps:

1. In the lumen: margination, rolling, and adhesion to endothelium

2. Migration across the endothelium and vessel wall
3. Migration in the tissues toward a chemotactic stimulus
 A. margination, rolling, and adhesion to endothelium

• In normally flowing blood in venules, red cells are confined to a

central axial column, displacing the leukocytes toward the wall
of the vessel.

• in inflammation :blood flow slows early (stasis), and more white

cells assume a peripheral position along the endothelial surface.
This process of leukocyte redistribution is called margination.

• individual and then rows of leukocytes adhere transiently to the

endothelium, detach and bind again, thus rolling on the vessel
wall. The cells finally come to rest at some point where they
adhere firmly (resembling pebbles over which a stream runs
without disturbing them).
 initial rolling interactions are mediated by a family of proteins
called selectins.
There are three types of selectins
i. E-selectin: endothelium
ii. P-selectin : plateletes, endothelium
iii. L-selectins: leukocytes

 On the leukocytes the ligands for selectins are sialylated

oligosaccharides bound to mucin-like glycoprotein backbones.
 The expression of selectins and their ligands is regulated by
cytokines produced in response to infection and injury.
• Leukocytes express L-selectin at the tips of their microvilli and also
express ligands for E- and P-selectins, all of which bind to the
complementary molecules on the endothelial cells.

• These are low-affinity interactions with a fast off-rate, and they are
easily disrupted by the flowing blood. As a result, the bound
leukocytes bind, detach, and bind again, and begin to roll along the
endothelial surface
Regulation of expression of endothelial and leukocyte adhesion molecules

• Tissue macrophages, mast cells, and endothelial cells that encounter

microbes and dead tissues respond by secreting several cytokines, including
tumor necrosis factor (TNF), interleukin-1 (IL-1), and 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 E-selectin and the
ligands for L-selectin.

• Other mediators such as histamine, thrombin, and platelet-activating factor

(PAF),stimulate the redistribution of P-selectin from its normal intracellular
stores in endothelial cell granules (called Weibel-Palade bodies) to the cell
surface.
Regulation of expression of endothelial
and leukocyte adhesion molecules
• A, Redistribution of P-selectin
from intracellular stores to the
cell surface.

• B, Increased surface expression

of selectins and ligands for
integrins upon cytokine activation
of endothelium.

• C, Increased binding avidity of

integrins induced by chemokines.
Clustering of integrins contributes
to their increased binding avidity.
 Leukocyte Migration through Endothelium
• Also called transmigration or diapedesis.

 Chemokines act on the adherent leukocytes and stimulate the

cells to migrate toward the site of injury or infection where the
chemokines are being produced.

 Occurs after firm adhesion within the system of venules and

capillaries via PECAM-1(CD31)
(Platelet Endothelial cell adhesion molecule ) on endothelial cells,
neutrophils, monocytes/macrophages,and lymphocytes
The multistep process of leukocyte migration
through blood vessels
 Leukocyte Migration through Endothelium
• After traversing the endothelium, leukocytes pierce the
basement membrane, probably by secreting collagenases, and
enter the extravascular tissue.

• The cells then migrate toward the chemotactic gradient created

by chemokines and accumulate in the extravascular site.
 Chemotaxis of Leukocytes
• After exiting the circulation, leukocytes emigrate in tissues toward the
site of injury by a process called chemotaxis.

Both exogenous and endogenous substances can act as chemoattractants.

 The most common exogenous agents are bacterial products, including

peptides that possess an N-formylmethionine terminal amino acid, and
some lipids.

 Endogenous chemoattractants include several chemical mediators: (1)

cytokines, particularly those of the chemokine family (e.g., IL-8) (2)
components of the complement system, particularly C5a
(3) arachidonic acid (AA) metabolites, mainly leukotriene B4 (LTB4).

• All these chemotactic agents bind to a specific seven-transmembrane G

protein–coupled receptors on the surface of leukocytes.
 Chemotaxis of Leukocytes increase cytosolic calcium and
Chemotactic agents activate
binds G protein– small guanosine triphosphatases
of the Rac/Rho/cdc42
coupled receptors family

These signals induce

polymerization of
actin

increased amounts of The leukocyte moves by extending

polymerized actin at the filopodia that pull the back of the
cell in the direction of extension,
leading edge of the cell and much as an automobile with front-
localization wheel drive is pulled by the wheels
of myosin filaments at the back in front
Scanning electron
micrograph of a
moving leukocyte
in culture showing a
filopodium (upper left)
and a trailing tail.
 The nature of the leukocyte infiltrate

during the
•Neutrophils
first 6 to predominate
24 hours

in 24 to •Replaced by
48 hours. Monocytes
Reasons account for the early appearance of
neutrophils

 The are more numerous in the blood.

 they respond more rapidly to chemokines.
 they may attach more firmly to the adhesion molecules that are
rapidly induced on endothelial cells, such as P- and E-selectins.

 After entering tissues, neutrophils are short-lived; they undergo

apoptosis and disappear after 24 to 48 hours.

 Monocytes not only survive longer but may proliferate in the

tissues, and thus become the dominant population in chronic
inflammatory reactions
 Exceptions to this pattern of cellular
infiltration

Pseudomona •cellular infiltrate is dominated by continuously

recruited neutrophils for several days.
s bacteria
Viral •lymphocytes may be the first
infections cells to arrive

some •eosinophils may be the main

hypersensitivity
reactions cell type.
Recognition of Microbes and Dead Tissues
• Leukocytes express several receptors that recognize external stimuli and
deliver activating signals:
 Recognition of Microbes and Dead Tissues
1.Receptors for microbial products: Toll-like receptors
(TLRs):
 recognize components of different types of microbes.
 Different TLRs play essential roles in cellular
responses to bacterial lipopolysaccharide (LPS, or
endotoxin), other bacterial proteoglycans and lipids,
and unmethylated CpG nucleotides.

 TLRs are present on the cell surface and in the

endosomal vesicles of leukocytes.
 they are able to sense products of extracellular and
ingested microbes.
 Function through receptor-associated kinases to
stimulate the production of microbicidal substances
and cytokines by the leukocytes.
 Recognition of Microbes and Dead Tissues

2. G protein–coupled receptors:

 found on neutrophils, macrophages, and most

other types of leukocytes
 Recognize short bacterial peptides containing
N-formylmethionyl residues
 all bacterial proteins are initiated by N-
formylmethionine.
 this receptor enables neutrophils to detect
and respond to bacterial proteins
 Binding of ligands, such as microbial products
and mediators, to the G protein–coupled
receptors induces migration of the cells from
the blood through the endothelium and
production of microbicidal substances by
activation of the respiratory burst.
 Recognition of Microbes and Dead Tissues

3. Receptors for opsonins:

 Leukocytes express receptors for proteins
that coat microbes
 One of the most efficient ways of
enhancing the phagocytosis of particles is
coating the particles with IgG antibodies
specific for the particles, which are then
recognized by the high-affinity Fcγ
receptor of phagocytes, called FcγRI .
 The binding of opsonized particles to
leukocyte Fc promotes phagocytosis of
the particles and activates the cells.
 Recognition of Microbes and Dead Tissues
4. Receptors for cytokines:
 Leukocytes express receptors for
cytokines that are produced in
response to microbes.
 One of the most important of
these cytokines is interferon-γ (ΙFN-
γ), which is secreted by natural
killer cells reacting to microbes and
by antigen-activated T lymphocytes
during adaptive immune
responses.

 IFN-γ is the major macrophage-

activating cytokine.
 Removal of the
Offending Agents
 The functional responses that are
most important for destruction of
microbes and other offenders are
phagocytosis and intracellular
killing.

 destruction of ingested particles

within the phagolysosomes by
lysosomal enzymes and by reactive
oxygen and nitrogen species.

 The microbicidal products

generated from superoxide (O2•− )
are hypochlorite (HOCl•) and
hydroxyl radical (•OH), and from
nitric oxide (NO) it is peroxynitrite
(OONO•).
 Other Functional Responses of
Activated Leukocytes

• Different stimuli activate monocytes/macrophages to develop into functionally distinct

populations:

I. Classically activated macrophages: are induced by microbial products and cytokines,

particularly IFN-γ, and are microbicidal and involved in potentially harmful inflammation.

II. Alternatively activated macrophages: are induced by other cytokines and in response to
helminths and are important in tissue repair and the resolution of inflammation
 Release of Leukocyte Products and
Leukocyte-Mediated Tissue Injury
• Leukocytes are important causes of injury to normal cells and
tissues under several circumstances:
A. As part of a normal defense reaction against infectious microbes,
when adjacent tissues suffer “collateral damage.” and In some
infections that are difficult to eradicate, such as tuberculosis and
certain viral diseases, the prolonged host response contributes
more to the pathology than does the microbe itself.

B. autoimmune diseases: When the inflammatory response is

inappropriately directed against host tissues.

C. allergic diseases: When the host reacts excessively against usually

harmless environmental substances.
 Release of Leukocyte Products and
Leukocyte-Mediated Tissue Injury
 once the leukocytes are activated, their effector mechanisms do not
distinguish between offender and host.
 During activation and phagocytosis, neutrophils and macrophages release
microbicidal and other products not only within the phagolysosome but
also into the extracellular space.
 The most important of these substances are lysosomal enzymes, present in
the granules, and reactive oxygen and nitrogen species.
 These released substances are capable of damaging normal cells and
vascular endothelium, and may thus amplify the effects of the initial
injurious agent.
 Defects in Leukocyte Function
 inherited or acquired.
 lead to increased vulnerability to infections.

• These include the following:

I. Inherited defects in leukocyte adhesion: genetic defects of integrins and
selectin-ligands leukocyte adhesion deficiencies types 1 and 2 recurrent
bacterial infections.

II. Inherited defects in phagolysosome function: Chédiak-Higashi syndrome(AR)

III. Inherited defects in microbicidal activity: chronic granulomatous disease

inherited defects in the genes encoding components of phagocyte oxidase,
which generates O2•−.

IV. Acquired deficiencies: e.g., leukemias / radiation and chemotherapybone

marrow suppressiondecreased production of leukocytes.
Defects in leukocyte functions
 TERMINATION OF THE ACUTE
INFLAMMATORY RESPONSE

• inflammation declines simply because the mediators of inflammation

are produced in rapid bursts, have short half-lives, and are degraded
after their release.
• Neutrophils also have short half-lives in tissues and die by apoptosis a
few hours after leaving the blood
• the process also triggers a variety of stop signals that serve to actively
terminate the reaction:

1. active termination
mechanisms include a switch proinflammatory
in the type of arachidonic leukotrienes
acid metabolite produced,
from proinflammatory
anti-inflammatory
leukotrienes to anti- lipoxins
inflammatory lipoxins
 TERMINATION OF THE ACUTE
INFLAMMATORY RESPONSE
2.liberation of anti-
inflammatory cytokines,
including transforming
growth factor-β (TGF-β)
and IL-10, from
macrophages and other
cells
Mediators of Inflammation
 Mediators of Inflammation
• Mediators are generated either from cells or from plasma proteins.

Cell-derived mediators Plasma-derived mediators

(platelets, neutrophils,
monocytes/macrophages, mast cells, mesenchymal (e.g., complement
cells <endothelium, smooth muscle, fibroblasts> and proteins, kinins)
most epithelia)

activated,
usually by
Or are present in a series of
secreted by the
synthesized de proteolyti
granule produced circulatio
sequestered exocytosis (e.g., novo (e.g., c
in intracellular prostaglandins, mainly in n as
histamine in cleavages,
granules cytokines) in the liver inactive
mast cell
response to a precursor to acquire
granules) their
stimulus s
biologic
properties
Mediators of Inflammation
 Mediators of Inflammation
• Active mediators are produced in response to various stimuli.(e.g. microbial
products, substances released from necrotic cells, the proteins of the
complement, kinin, and coagulation systems, which are themselves
activated by microbes and damaged tissues.

• One mediator can stimulate the release of other mediators(e.g. cytokine TNF
acts on endothelial cells stimulate the production of another cytokine, IL-
1, and many chemokines).

• Mediators vary in their range of cellular targets(can act on one or a few

target cell types, can have diverse targets)

• Once activated and released from the cell, most of these mediators are
short-lived. They quickly decay (e.g., arachidonic acid metabolites) or are
inactivated by enzymes (e.g., kininase inactivates bradykinin), or they are
otherwise scavenged (e.g., antioxidants scavenge toxic oxygen metabolites)
 CELL-DERIVED MEDIATORS
Vasoactive Amines: Histamine and
Serotonin
• stored as preformed molecules in cells
• the first mediators to be released during inflammation

• richest sources of histamine are the mast cells that are

normally present in the connective tissue adjacent to blood
vessels. (also found in blood basophils and platelets).

• released by mast cell degranulation in response to a variety of

stimuli: (1) physical injury such as trauma, (2) binding of
antibodies to mast cells, which underlies allergic reactions ;(3)
fragments of complement called anaphylatoxins (C3a and C5a);
(4) histamine-releasing proteins derived from leukocytes; (5)
neuropeptides (e.g., substance P); and (6) cytokines (IL-1, IL-8)
 CELL-DERIVED MEDIATORS
Vasoactive Amines: Histamine
• Histamine causes dilation of
arterioles and increases the
permeability of venules.
• It is the principal mediator of the
immediate transient phase of
increased vascular permeability,
producing interendothelial gaps in
venules.
• Its vasoactive effects are mediated
mainly via binding to H1 receptors
on microvascular endothelial cells.
 CELL-DERIVED MEDIATORS
Vasoactive Amines: Serotonin
(5-hydroxytryptamine)

• preformed vasoactive mediator

• It is present in platelets and certain neuroendocrine cells
• Release of serotonin (and histamine) from platelets is
stimulated when platelets aggregate after contact with
collagen, thrombin, adenosine diphosphate, and antigen-
antibody complexes

• the platelet release reaction, which is a key component of

coagulation, also results in increased vascular permeability.
This is one of several links between clotting and
inflammation.
 Arachidonic Acid (AA) Metabolites:
Prostaglandins, Leukotrienes,
and Lipoxins
 cells are activated by diverse stimuli( such as microbial products and
various mediators of inflammation) membrane AA is rapidly
converted by the actions of enzymes to produce prostaglandins
and leukotrienes.
 Serve as intracellular or extracellular signals to affect a variety
of biologic processes, including inflammation and hemostasis.
 Arachidonic Acid (AA) Metabolites:
Prostaglandins, Leukotrienes,
and Lipoxins
• AA-derived mediators, also called eicosanoids, are synthesized by two
major classes of enzymes: cyclooxygenases (which generate prostaglandins)
and lipoxygenases (which produce leukotrienes and lipoxins) .
• Eicosanoids bind to G protein–coupled receptors on many cell types and can
mediate virtually every step of inflammation
 Prostaglandins (PGs)
• produced by mast cells, macrophages, endothelial cells, and
many other cell types.

• produced by the actions of two cyclooxgenases, constitutively

expressed COX-1 and the inducible enzyme COX-2.

• Prostaglandins are divided into series based on structural

features as coded by a letter (PGD, PGE, PGF, PGG, and PGH)
and a subscript numeral (e.g., 1, 2), which indicates the
number of double bonds in the compound.

• PGD2 is the major prostaglandin made by mast cells; along

with PGE2 (which is more widely distributed), it causes
vasodilation and increases the permeability of post-capillary
venules, thus potentiating edema formation.
 Prostaglandins (PGs)
• PGF2α stimulates the contraction of uterine and bronchial
smooth muscle and small arterioles, and PGD2 is a
chemoattractant for neutrophils.

• the prostaglandins are involved in the pathogenesis of pain

and fever in inflammation.

• PGE2 is hyperalgesic and makes the skin hypersensitive to

painful stimuli, such as intradermal injection of suboptimal
concentrations of histamine and bradykinin. It is involved in
cytokine-induced fever during infections
 leukotrienes
 5-lipoxygenase enzyme converts AA to the precursor of the
leukotrienes.

 LTB4 is a potent chemotactic agent and activator of neutrophils,

causing aggregation and adhesion of the cells to venular
endothelium, generation of ROS, and release of lysosomal
enzymes.

 The cysteinyl containing leukotrienes C4, D4, and E4 (LTC4, LTD4,

LTE4) cause intense vasoconstriction, bronchospasm (important
in asthma), and increased vascular permeability.

 Leukotrienes are much more potent than is histamine in

increasing vascular permeability and causing bronchospasm.
 Lipoxins
• generated from AA by the lipoxygenase pathway.

• unlike prostaglandins and leukotrienes, the lipoxins are inhibitors

of inflammation.

• They are unusual in that two cell populations are required for the
transcellular biosynthesis of these mediators.

• The principal actions of lipoxins are to inhibit leukocyte

recruitment and the cellular components of inflammation.

• Inverse relationship between the production of lipoxin and

leukotrienes, that the lipoxins may be endogenous negative
regulators of leukotrienes  play a role in the resolution of
inflammation.
 Anti-inflammatory drugs work by inhibiting the
synthesis of eicosanoids

Cyclooxygenase inhibitors:
• aspirin and other
nonsteroidal anti-
inflammatory drugs
(NSAIDs), such as
indomethacin.
• They inhibit both COX-1
and COX-2  inhibit
prostaglandin synthesis;
aspirin does this by
irreversibly acetylating and
inactivating
cyclooxygenases.
 Anti-inflammatory drugs work by inhibiting the
synthesis of eicosanoids

Lipoxygenase inhibitors:
• 5-lipoxygenase is not
affected by NSAIDs.
• Pharmacologic agents
that inhibit leukotriene
production (e.g.
Zileuton) or block
leukotriene receptors
(e.g. Montelukast) are
useful in the treatment
of asthma.
 Anti-inflammatory drugs work by inhibiting
the synthesis of eicosanoids
Broad-spectrum inhibitors include
corticosteroids:
• These powerful anti-inflammatory agents may
act by reducing the transcription of genes
encoding COX-2, phospholipase A2, pro-infl
ammatory cytokines (such as IL-1 and TNF),
and iNOS.
 Another approach to manipulating inflammatory responses :
• By modifying the intake and content of dietary lipids by
increasing the consumption of fish oil.

.
the polyunsaturated
fatty acids in fish oil
serve as poor substrates
for conversion to active
metabolites by both the
cyclooxygenase and
lipoxygenase pathways
but are excellent
substrates for the
production of anti-
inflammatory lipid
products called resolvins
and protectins
 Platelet-Activating Factor (PAF)
 another phospholipid-derived mediator.
 multiple inflammatory effects.
 Produced by a variety of cell types, including platelets
themselves, basophils, mast cells, neutrophils, macrophages,
and endothelial cells.

 PAF causes : platelet aggregation, vasoconstriction and

bronchoconstriction, and at extremely low concentrations it
induces vasodilation and increased venular permeability with a
potency 100 to 10,000 times greater than that of histamine.

 PAF also causes increased leukocyte adhesion to endothelium

(by enhancing integrin-mediated leukocyte binding),
chemotaxis, degranulation, and the oxidative burst.
 Reactive Oxygen Species
• released extracellularly from leukocytes after exposure to microbes, chemokines,
and immune complexes, or following a phagocytic challenge.
• Their production is dependent, on the activation of the NADPH oxidase system.
• Superoxide anion (O2•−), hydrogen peroxide (H2O2), and hydroxyl radical (•OH)
are the major species produced within cells, and O2•− can combine with NO to
form reactive nitrogen species
• implicated in the following responses in inflammation:
Endothelial cell damage, with •Adherent neutrophils, when activated, not only
resultant increased vascular produce their own toxic species but also stimulate
permeability.
production of ROS in the endothelial cells.

Injury to other •(parenchymal cells, red

cell types blood cells)
Inactivation of •unopposed protease activity, with increase destruction of
extracellular matrix
antiproteases, such •In the lung, such inhibition of anti-proteases contributes to
as α1-antitrypsin. destruction of elastic tissues, as in emphysema
 Antioxidant mechanisms
• tissue fluids, and host cells possess antioxidant mechanisms
that protect against these potentially harmful oxygen-derived
radicals.
The enzyme The enzyme
superoxide catalase
dismutase (detoxifies H2O2)

Glutathione The copper-

peroxidase(another containing serum
powerful H2O2 protein
detoxifier) ceruloplasmin

the iron-free
fraction of serum
 Nitric Oxide (NO)
 NO is a soluble gas
 produced by endothelial cells, macrophages and some neurons in the brain.
 It acts in a paracrine manner on target cells through induction of cyclic
guanosine monophosphate, which, in turn, initiates a series of intracellular
events leading to a response, such as the relaxation of vascular smooth
muscle cells.
 the in vivo half-life of NO is only seconds, the gas acts only on cells in close
proximity to where it is produced.
 Nitric Oxide (NO)
 NO is synthesized from l-
arginine by the enzyme nitric
oxide synthase (NOS).
 There are three different
types of NOS: endothelial
(eNOS), neuronal (nNOS), and
inducible (iNOS)
 NO has dual actions in
inflammation: it relaxes
vascular smooth muscle and
promotes vasodilation, thus
contributing to the vascular
reaction, but it is also an
inhibitor of the cellular
component of inflammatory
responses
 Cytokines and Chemokines

• proteins produced by many cell types (principally activated

lymphocytes ,macrophages, and endothelial, epithelial, connective
tissue cells) that modulate the functions of other cell types.
Principal local and systemic actions of tumor necrosis
factor (TNF) and interleukin-1 (IL-1)
 Lysosomal Constituents of Leukocytes
•Neutrophils and monocytes contain lysosomal granules, which,
when released, may contribute to the inflammatory response.
• Because of the destructive effects of
lysosomal enzymes, the initial
leukocytic infiltration, if unchecked, can
potentiate further inflammation and
tissue damage.

• These harmful proteases, are held in

check by a system of antiproteases in
the serum and tissue fuids.
• among these is α1-antitrypsin, which
is the major inhibitor of neutrophil
elastase. A deficiency of these
inhibitors may lead to sustained action
of leukocyte proteases, as is the case in
patients with α1-antitrypsin deficiency
 Neuropeptides
• Neuropeptides are secreted by sensory nerves and various
leukocytes, and play a role in the initiation and propagation of
inflammatory response.

• The small peptides, such as substance P and neurokinin A, belong to

a family of tachykinin neuropeptides produced in the central and
peripheral nervous systems.

• Nerve fibers containing substance P are prominent in the lung and

gastrointestinal tract.
• Substance P has many biologic functions, including the transmission
of pain signals, regulation of blood pressure, stimulation of
secretion by endocrine cells, and increasing vascular permeability.
 PLASMA PROTEIN–DERIVED MEDIATORS

• Three interrelated systems: the complement,

kinin, and clotting systems.

Complement

Kinin

clotting systems
 Complement System
• >20 proteins
• C1-C9 Increased
chemotaxis
vascular opsonization
permeability

Complem
ent
 The activation and functions of the complement system

Activation of complement by different pathways leads to cleavage of C3.

The functions of the complement system are mediated by breakdown products
of C3 and other complement proteins, and by the membrane attack complex
(MAC).
 The classical
pathway

• triggered by fixation of
C1 to antibody (IgM or
IgG) that has combined
with antigen
 Alternative pathway
can be triggered by:
• microbial surface
molecules (e.g.,
endotoxin, or LPS),
complex
polysaccharides, cobra
venom, and other
substances, in the
absence of antibody
 The lectin pathway
• plasma mannose-binding lectin binds to
carbohydrates on microbes and directly
activates C1.
 Overview of the complement system
All pathways lead to the
formation of an active enzyme
called the C3 convertase, which
splits C3 into two functionally
distinct fragments, C3a and C3b.

C3a is released, and C3b

becomes covalently attached to
the cell or molecule where
complement is being activated.

 More C3b then binds to the

previously generated fragments to
form C5 convertase, which cleaves
C5 to release C5a and leave C5b
attached to the cell surface.

 C5b binds the late components

(C6–C9), culminating in the
formation of the membrane attack
complex (MAC, composed of
multiple C9 molecules)
 Coagulation and Kinin Systems
• Inflammation and blood clotting are often intertwined, with each
promoting the other.
• The clotting system is divided into two pathways that converge: the
activation of thrombin and the formation of fibrin

XIIa is inducing fibrin clot

formation, and activates the
fbrinolytic system. This
cascade counterbalances
clotting by cleaving fibrin,
thereby solubilizing
the clot.
activated upon contact with
negatively charged surfaces when
vascular permeability increases
and plasma proteins leak into the
extravascular space and come into
contact with collagen, or when it
comes into contact with basement
membranes exposed as a
result of endothelial
damage.
 Kinins
 Kinins are vasoactive peptides derived from plasma proteins,
called kininogens, by the action of specific proteases called
kallikreins.
 Bradykinin increases
vascular permeability and
causes contraction of
smooth muscle, dilation of
blood vessels, and pain
when injected into the skin.
These effects are similar to
those of histamine.

 The action of bradykinin

is short-lived, because it is
quickly inactivated by an
enzyme called kininase
 conclusions
• Bradykinin, C3a, and C5a (as mediators of increased vascular permeability); C5a
(as the mediator of chemotaxis);and thrombin (which has effects on endothelial
cells and many other cell types) are likely to be the most important in vivo.

• C3a and C5a can be generated by several types of reactions: (1) immunologic
reactions, involving antibodies and complement (the classical pathway); (2)
activation of the alternative and lectin complement pathways by microbes, in
the absence of antibodies; and (3) agents not directly related to immune
responses, such as plasmin, kallikrein, and some serine proteases found in
normal tissue.

• Activated Hageman factor (factor XIIa) initiates four systems involved in the
inflammatory response: (1) the kinin system, which produces vasoactive kinins;
(2) the clotting system, which induces formation of thrombin, which has
inflammatory properties; (3) the fibrinolytic system, which produces plasmin and
degrades fibrin to produce fibrinopeptides, which induce inflammation; and (4)
the complement system, which produces anaphylatoxins and other mediators.
Some of the products of this initiation—particularly kallikrein—can, by feedback,
activate Hageman factor, resulting in amplification of the reaction.
Role of Mediators in Different Reactions of Inflammation
 Outcomes of Acute Inflammation
all acute inflammatory reactions may have one of three outcomes:

Healing by connective tissue

Complete resolution replacement Chronic inflammation
(fibrosis/organization)

occurs after substantial the acute inflammatory

tissue destruction, response cannot be
resolved, as a result of
eliminating the when the inflammatory
either the persistence of
injurious stimulus injury involves tissues the injurious agent or some
that are incapable of interference with the
regeneration normal process of healing

abundant fibrin e.g.

removal of cellular
exudation in tissue or pneumoniachronic
debris and microbes
serous cavities lung abscess
by macrophages, and
(pleura, peritoneum) Peptic ulcer of the
resorption of edema
that cannot be duodenum or
fluid by lymphatics
adequately cleared. stomach
 Morphologic Patterns of Acute Inflammation
• The morphologic hallmarks of all acute inflammatory
reactions are dilation of small blood vessels, slowing of blood
flow, and accumulation of leukocytes and fluid in the
extravascular tissue.
 SEROUS INFLAMMATION
• 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.
• Accumulation of fluid in these cavities is called an effusion.

The skin blister resulting from a

burn or viral infection represents a
large accumulation of serous fluid,
either within or immediately
beneath the epidermis of the skin.
 FIBRINOUS INFLAMMATION
 With greater increase in vascular permeability, large molecules such as
fibrinogen pass the vascular barrier, and fibrin is formed and deposited
in the extracellular space.
 A fibrinous exudate develops when the vascular leaks are large or there is
a local procoagulant stimulus (e.g., cancer cells).
 A fibrinous exudate is characteristic of inflammation in the lining of body
cavities, such as the meninges, pericardium and pleura.
 Histologically, fibrin appears as an eosinophilic meshwork of threads or
sometimes as an amorphous coagulum.
 Fibrinous exudates may be removed by fibrinolysis and clearing of other
debris by macrophages.
 If the fibrin is not removed over time it may stimulate the ingrowth of
fibroblasts and blood vessels and thus lead to scarring.
 SUPPURATIVE OR PURULENT
INFLAMMATION; ABSCESS
• characterized by the production of large amounts of pus or purulent exudate
consisting of neutrophils, liquefactive necrosis, and edema fluid.
• Produced by pyogenic (pus-producing) bacteria (e.g., staphylococci)
• common example of an acute suppurative inflammation is acute appendicitis.
 Abscesses :
 are localized collections of purulent inflammatory tissue caused by suppuration
 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. around this
necrotic focus a zone of
preserved neutrophils,
and outside this region
vascular dilation and
parenchymal and
fbroblastic proliferation
occur.
 ULCERS
• An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is
produced by the sloughing (shedding) of inflamed necrotic tissue
• can occur only when tissue necrosis and resultant inflammation exist on or near a
surface
most commonly encountered in:
(1) the mucosa of the mouth, stomach, intestines, or genitourinary tract.
(2) the skin and subcutaneous tissue of the lower extremities in older persons who
have circulatory disturbances that predispose to extensive ischemic necrosis.
• Ulcerations are best exemplified by peptic ulcer of the stomach or duodenum, in
which acute and chronic inflammation coexist.
• During the acute stage there is intense polymorphonuclear infiltration and vascular
dilation in the margins of the defect. With chronicity, the margins and base of the
ulcer develop fibroblastic proliferation, scarring, and the accumulation of
lymphocytes, macrophages, and plasma cells.
 Summary of Acute Inflammation
The sequence of events

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 The clinical and pathologic manifestations of the inflammatory
The vascular phenomena
(redness (rubor), warmth
(calor), and swelling (tumor)
•increased blood flow to the
injured area, resulting mainly
from arteriolar dilation and
opening of capillary beds
induced by mediators such as
histamine.
•Increased vascular
permeability results in the
accumulation of protein rich
extravascular fluid, which
forms the exudate.
response
Circulating
leukocytes
•Initially predominantly
neutrophils, adhere to the
endothelium via adhesion
molecules, traverse the
endothelium, and migrate to
the site of injury under the
influence of chemotactic
agents.
•Leukocytes are activated by
the offending agent and by
endogenous mediators.
tissue damage
(pain)
•Activated Leukocytes may
release toxic metabolites
and proteases
extracellularly, causing
tissue damage.
• During the damage, and in
part as a result of the
liberation of prostaglandins,
neuropeptides, and
cytokines, one of the local
symptoms is pain (dolor).
 Chronic Inflammation
• prolonged duration (weeks or months)

• CAUSES :
I. Persistent infections by microorganisms that are difficult to eradicate.
e.g. mycobacteria, and certain viruses, fungi, and parasites.
II. Immune-mediated inflammatory diseases: In these diseases,
autoantigens evoke a self-perpetuating immune reaction that results
in chronic tissue damage and inflammation :e.g.
 autoimmune diseases :rheumatoid arthritis and multiple sclerosis
 unregulated immune responses against microbes, as in inflammatory
bowel disease.
 allergic diseases :Immune responses against common environmental
substances , such as bronchial asthma

III. Prolonged exposure to potentially toxic agents, either exogenous or

endogenous. E.g. silicosis
 MORPHOLOGIC FEATURES

• Infiltration with mononuclear cells, which include

macrophages, lymphocytes, and plasma cells

• Tissue destruction, induced by the persistent offending

agent or by the inflammatory cells

• Attempts at healing by connective tissue replacement

of damaged tissue, accomplished by proliferation of
small blood vessels (angiogenesis) and, in particular,
fibrosis
 ROLE OF MACROPHAGES IN
CHRONIC INFLAMMATION
 The macrophage is the dominant cellular player in chronic
inflammation .
 eliminate injurious agents such as microbes.
 initiate the process of repair.
 responsible for much of the tissue injury in chronic inflammation.
 The roles of activated
macrophages in chronic
inflammation.
• Macrophages are activated by
nonimmunologic stimuli such as
endotoxin or by cytokines from
immune-activated T cells
(particularly IFN-γ).

• In short-lived inflammation, if the

irritant is eliminated, macrophages
eventually disappear (either dying
off or making their way into the
lymphatics and lymph nodes).

• In chronic inflammation,
macrophage accumulation persists,
as a result of continuous recruitment
from the circulation and local
proliferation at the site of
inflammation
 OTHER CELLS IN CHRONIC
INFLAMMATION
Lymphocytes
• mobilized in both antibody-mediated and cell-mediated immune
reactions.
• Antigen-stimulated T and B cells use various adhesion molecule pairs
(selectins, integrins and their ligands) and chemokines to migrate into
inflammatory sites.

• Cytokines from activated macrophages, mainly TNF, IL-1, and

chemokines, promote leukocyte recruitment, setting the stage for
persistence of the inflammatory response.

• Lymphocytes and macrophages interact in a bidirectional way:

Macrophages display antigens to T cells and produce membrane
molecules (costimulators) and cytokines (notably IL-12) that stimulate
T-cell responses
 Macrophage-lymphocyte interactions in
chronic inflammation.
• Activated T cells produce
cytokines that recruit
macrophages (TNF, IL-17,
chemokines) and others
that activate macrophages
(IFNγ). Different subsets of
T cells (called TH1 and
TH17) may produce
different sets of cytokines.

• Activated macrophages in
turn stimulate T cells by
presenting antigens and via
cytokines (such as IL-12).
 OTHER CELLS IN CHRONIC
INFLAMMATION
Eosinophils
• abundant in immune reactions mediated by IgE and in parasitic
infections.

• A chemokine that is especially important for eosinophil

recruitment is eotaxin.

• Eosinophils have granules that contain major basic protein, a

highly cationic protein that is toxic to parasites but also causes
lysis of mammalian epithelial cells.

• This is why eosinophils are of benefit in controlling parasitic

infections, but they contribute to tissue damage in immune
reactions such as allergies.
A focus of inflammation showing numerous eosinophils
 OTHER CELLS IN CHRONIC
INFLAMMATION
Mast cells
• widely distributed in connective tissues.
• participate in both acute and chronic inflammatory reactions.

• express on their surface the receptor (FcεRI) that binds the Fc

portion of IgE antibody.
• In immediate hypersensitivity reactions, IgE antibodies bound to
the cells’ Fc receptors specifically recognize antigen, and the cells
degranulate and release mediators, such as histamine and
prostaglandins .
• This type of response occurs during allergic reactions to foods,
insect venom, or drugs, sometimes with catastrophic results (e.g.
anaphylactic shock).
• they secrete a plethora of cytokines, that have the ability to both
promote and limit inflammatory reactions in different situations.
 OTHER CELLS IN CHRONIC
INFLAMMATION
neutrophils
 Although neutrophils are characteristic of acute
inflammation, many forms of chronic inflammation, lasting
for months, continue to show large numbers of neutrophils.

 induced either by persistent microbes or by mediators

produced by activated macrophages and T lymphocytes.

 In chronic bacterial infection of bone (osteomyelitis), a

neutrophilic exudate can persist for many months.

 Neutrophils are also important in the chronic damage

induced in lungs by smoking and other irritant stimuli.
• In addition to cellular infltrates, growth of
blood vessels and lymphatic vessels is often
prominent in chronic inflammatory reactions.

• This growth of vessels is stimulated by growth

factors, such as VEGF, produced by
macrophages and endothelial cells
 GRANULOMATOUS INFLAMMATION
• a distinctive pattern of chronic inflammation.

• a limited number of infectious and some noninfectious

conditions.

• a granuloma is a cellular attempt to contain an offending agent

that is difficult to eradicate.

• there is often strong activation of T lymphocytes leading to

macrophage activation, which can cause injury to normal
tissues.
 GRANULOMATOUS INFLAMMATION
• Tuberculosis , sarcoidosis, cat-scratch disease,
lymphogranuloma inguinale, leprosy, brucellosis,
syphilis, some mycotic infections, berylliosis, reactions
of irritant lipids, and some autoimmune diseases
• A granuloma is 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 leukocytes,
principally lymphocytes and
occasionally plasma cells.

Macrophages
(transformed
into epithelium
like cells)
• In the usual hematoxylin and eosin–stained
tissue sections, the epithelioid cells have a
pale pink granular cytoplasm with indistinct
cell boundaries, often appearing to merge into
one another.

• The nucleus is less dense than that of a

lymphocyte, is oval or elongate, and may show
folding of the nuclear membrane.

• Older granulomas develop an enclosing rim of

fibroblasts and connective tissue.

• Frequently, epithelioid cells fuse to form giant

cells in the periphery or sometimes in the -Typical tuberculous granuloma showing
center of granulomas. These giant cells may an area of central necrosis surrounded by
attain diameters of 40 to 50 μm. They have a multiple Langhans-type giant cells,
large mass of cytoplasm containing 20 or more epithelioid cells, and lymphocytes.
small nuclei arranged either peripherally
(Langhans-type giant cell) or haphazardly
(foreign body–type giant cell)
 There are two types of granulomas, which differ in their pathogenesis:

Foreign body granulomas

Around meterials that are large enough to preclude phagocytosis by a single

macrophage and do not incite any specific inflammatory or immune response.
(e.g.talc, sutures)

Epithelioid cells and giant cells are apposed to the surface of the foreign body
 ular
and
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proteins, protei
•In
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infections
•The
L
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 Other manifestations of the acute-
phase response
• increased pulse and blood pressure.

• decreased sweating, mainly because of

redirection of blood flow from cutaneous to deep
vascular beds, to minimize heat loss through the
skin; rigors (shivering), chills (search for warmth).

• anorexia, somnolence, and malaise, probably

because of the actions of cytokines on brain cells.
Severe bacterial infections (sepsis)
• large amounts of organisms and LPS in the
blood stimulate the production of enormous
quantities of several cytokines, notably TNF
and IL-1.

• High levels of cytokines cause various clinical

manifestation such as disseminated
intravascular coagulation, cardiovascular
failure, and metabolic disturbance, which are
described as septic shock.
 Consequences of Defective or
Excessive Inflammation

Defective • increased susceptibility to infections.

inflamma •delayed wound healing, because inflammation

is essential for clearing damaged tissues and
debris and provides the necessary stimulus to

tion
get the repair process started.

Excessive •Allergiesunregulated immune responses against

inflamma
commonly encountered environmental antigens.
•autoimmune diseasesimmune responses develop against
normally tolerated selfantigens.
•Prolonged inflammation and the fibrosis that accompanies it

tion
are also responsible for much of the pathology in many
infectious, metabolic, and other diseases.
• Thank you 