ACUTE AND CHRONIC INFLAMMATION

Overview of Inflammation
Inflammation is a complex reaction in tissues that consists mainly of responses of blood vessels and
leukocytes. The body's principal defenders against foreign invaders are plasma proteins and circulating
leukocytes (white blood cells), as well as tissue phagocytes that are derived from circulating cells. The
presence of proteins and leukocytes in the blood gives them the ability to home to any site where they
may be needed. Because invaders such as microbes and necrotic cells are typically present in tissues,
outside the circulation, it follows that the circulating cells and proteins have to be rapidly recruited to
these extravascular sites. The inflammatory response coordinates the reactions of vessels, leukocytes,
and plasma proteins to achieve this goal.
The vascular and cellular reactions of 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. Microbes, necrotic cells (whatever the cause of cell death) and even hypoxia can
trigger the elaboration of inflammatory mediators, and thus elicit inflammation.
Inflammation may be acute or chronic, depending on the nature of the stimulus and the effectiveness of
the initial reaction in eliminating the stimulus or the damaged tissues. Acute inflammation is rapid in
onset (typically minutes) and is of short duration, lasting for hours or a few days; its main characteristics
are the exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, predominantly
neutrophils (also called polymorphonuclear leukocytes). When acute inflammation is successful in
eliminating the offenders the reaction subsides, but if the response fails to clear the invaders it can
progress to a chronic phase. Chronic inflammation may follow acute inflammation or be insidious in
onset. It is of longer duration and is associated with the presence of lymphocytes and macrophages, the
proliferation of blood vessels, fibrosis, and tissue destruction.
Inflammation is terminated when the offending agent is eliminated.
The inflammatory response is closely intertwined with the process of repair. At the same time as
inflammation destroys, dilutes, and walls off the injurious agent, it sets into motion a series of events
that try to heal the damaged tissue. Repair begins during inflammation but reaches completion usually
after the injurious influence has been neutralized. In the process of repair the injured tissue is replaced
through regeneration of native parenchymal cells, by filling of the defect with fibrous tissue (scarring)
or, most commonly, by a combination of these two processes.
Inflammation may be harmful in some situations. Mechanisms designed to destroy foreign invaders and
necrotic tissues have an intrinsic ability to injure normal tissues. When inflammation is inappropriately
directed against self tissues or is not adequately controlled, it becomes the cause of injury and disease.
In fact, in clinical medicine, great attention is given to the damaging consequences of inflammation.
Inflammatory reactions underlie common chronic diseases, such as rheumatoid arthritis,
atherosclerosis, and lung fibrosis, as well as life-threatening hypersensitivity reactions to insect bites,
drugs, and toxins. For this reason our pharmacies abound with anti-inflammatory drugs, which ideally
would control the harmful sequelae of inflammation yet not interfere with its beneficial effects.

Historical Highlights
Celsus, a Roman writer of the first century AD, first listed the four cardinal signs of inflammation: rubor
(redness), tumor (swelling), calor (heat), and dolor (pain).1 These signs are typically more prominent in

acute inflammation than in chronic inflammation. A fifth clinical sign, loss of function (functio laesa), was
added by Rudolf Virchow.

Acute Inflammation
Acute inflammation is a rapid host response that serves to deliver leukocytes and plasma proteins, such
as antibodies, to sites of infection or tissue injury. Acute inflammation has three major components: (1)
alterations in vascular caliber that lead to an increase in blood flow, (2) structural changes in the
microvasculature that permit plasma proteins and leukocytes to leave the circulation, and (3) emigration
of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation
to eliminate the offending agent (Fig. 2-1).

STIMULI FOR ACUTE INFLAMMATION

Acute inflammatory reactions may be triggered by a variety of stimuli:
#Infections (bacterial, viral, fungal, parasitic) and microbial toxins are among the most common and
medically important causes of inflammation. Mammals possess many mechanisms for sensing the
presence of microbes. Among the most important receptors for microbial products are the family of
Toll-like receptors (TLRs), and several cytoplasmic receptors, which can detect bacteria, viruses, and
fungi .
#Tissue necrosis from any cause, including ischemia (as in a myocardial infarct), trauma, and physical
and chemical injury (e.g., thermal injury, as in burns or frostbite; irradiation; exposure to some
environmental chemicals). Several molecules released from necrotic cells are known to elicit
inflammation; these include uric acid; adenosine triphosphate, and even DNA when it is released into
the cytoplasm.Hypoxia, which often underlies cell injury, is also itself an inducer of the inflammatory
response.
#Foreign bodies (splinters, dirt, sutures) typically elicit inflammation because they cause traumatic tissue
injury or carry microbes.
#Immune reactions (also called hypersensitivity reactions) are reactions in which the normally protective
immune system damages the individual's own tissues. The injurious immune responses may be directed
against self antigens, causing autoimmune diseases
All inflammatory reactions share the same basic features, although different stimuli may induce
reactions with some distinctive characteristics. We first describe the typical sequence of events in acute
inflammation, and then the chemical mediators responsible for inflammation and the morphologic
appearance of these reactions.

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. An 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 (Fig. 2-2). In contrast, a transudate is a fluid with low protein content (most of which is
albumin), little or no cellular material, and low specific gravity. It is essentially an ultrafiltrate of blood
plasma that results from osmotic or hydrostatic imbalance across the vessel wall without an increase in

vascular permeability (Chapter 4). Edema denotes an excess of fluid in the interstitial tissue or serous
cavities; it can be either an exudate or a transudate. Pus, a purulent exudate, is an inflammatory exudate
rich in leukocytes (mostly neutrophils), the debris of dead cells and, in many cases, microbes.
The vascular reactions of acute inflammation consist of changes in the flow of blood and the
permeability of vessels.

Changes in Vascular Flow and Caliber

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 is quickly followed by increased permeability of the microvasculature, with the
outpouring of protein-rich fluid into the extravascular tissue.
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.
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, in a sequence that is described later.

Increased Vascular Permeability (Vascular Leakage)

A hallmark of acute inflammation is increased vascular permeability leading to the escape of a proteinrich exudate into the extravascular tissue, causing edema. Several mechanisms are responsible for the
increased vascular permeability (Fig. 2-3):
Contraction of endothelial cells resulting in increased interendothelial spaces is the most common
mechanism of vascular leakage and is elicited by histamine, bradykinin, leukotrienes, the neuropeptide
substance P, and many other chemical mediators.
Endothelial injury, resulting in endothelial cell necrosis and detachment.8 Direct damage to the
endothelium is encountered in severe injuries, for example, in burns.
Increased transport of fluids and proteins, called transcytosis, through the endothelial cell.
Although these mechanisms of increased vascular permeability are described separately, all
probably contribute in varying degrees in responses to most stimuli. For example, at different stages of a
thermal burn, leakage results from chemically mediated endothelial contraction and direct and
leukocyte-dependent endothelial injury.

Responses of Lymphatic Vessels

lymphatic vessels also participate in the response. The system of lymphatics and lymph nodes filters and
polices the extravascular fluids. Recall that 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. In addition to fluid, leukocytes and cell
debris, as well as microbes, may find their way into lymph. Lymphatic vessels, like blood vessels,
proliferate during inflammatory reactions to handle the increased load.11,12 The lymphatics may become
secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis).

REACTIONS OF LEUKOCYTES IN INFLAMMATION

The most important leukocytes in typical inflammatory reactions are the ones capable of phagocytosis,
namely neutrophils and macrophages. These leukocytes ingest and kill bacteria and other microbes, and
eliminate necrotic tissue and foreign substances.
The processes involving leukocytes in inflammation consist of: their recruitment from the blood into
extravascular tissues, recognition of microbes and necrotic tissues, and removal of the offending agent.

Recruitment of Leukocytes to Sites of Infection and Injury

The journey of leukocytes from the vessel lumen to the interstitial tissue, called extravasation, can be
divided into the following steps13 (Fig. 2-4):
1. In the lumen: margination, rolling, and adhesion to endothelium. Vascular endothelium in its
normal, unactivated state does not bind circulating cells or impede their passage. In
inflammation the endothelium is activated and can bind leukocytes, as a prelude to their exit
from the blood vessels.
2. Migration across the endothelium and vessel wall
3. Migration in the tissues toward a chemotactic stimulus.

Leukocyte 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. Because blood flow slows early in inflammation (stasis),
hemodynamic conditions change (wall shear stress decreases), and more white cells assume a
peripheral position along the endothelial surface. This process of leukocyte redistribution is called
margination. Subsequently, 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).
The initial rolling interactions are mediated by a family of proteins called selectins15,16 (Table 2-1). There
are three types of selectins: one expressed on leukocytes (L-selectin), one on endothelium (E-selectin),
and one in platelets and on endothelium (P-selectin). . The expression of selectins and their ligands is
regulated by cytokines produced in response to infection and injury. 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 (Fig. 2-5)

These weak rolling interactions slow down the leukocytes and give them the opportunity to bind more
firmly to the endothelium. Firm adhesion is mediated by a family of heterodimeric leukocyte surface
proteins called integrins21 (see Table 2-1).

Leukocyte Migration through Endothelium

The next step in the process of leukocyte recruitment is migration of the leukocytes through the
endothelium, called transmigration or diapedesis. Transmigration of leukocytes occurs mainly in postcapillary venules. Chemokines act on the adherent leukocytes and stimulate the cells to migrate through
interendothelial spaces toward the chemical concentration gradient, that is, toward the site of injury or
infection where the chemokines are being produced.

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. Endogenous chemoattractants include several
chemical mediators (described later): (1) cytokines, particularly those of the chemokine family (e.g., IL8); (2) components of the complement system, particularly C5a; and (3) arachidonic acid (AA)
metabolites, mainly leukotriene B4 (LTB4).

The nature of the leukocyte infiltrate varies with the age of the inflammatory response and the type
of stimulus. In most forms of acute inflammation neutrophils predominate in the inflammatory infiltrate
during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hours (Fig. 2-7). Several reasons
account for the early appearance of neutrophils: they are more numerous in the blood, they respond
more rapidly to chemokines, and 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. There are, however, exceptions to this pattern of cellular infiltration. In certain
infections-for example, those produced by Pseudomonas bacteria-the cellular infiltrate is dominated by
continuously recruited neutrophils for several days; in viral infections, lymphocytes may be the first cells
to arrive; in some hypersensitivity reactions, eosinophils may be the main cell type.

Recognition of Microbes and Dead Tissues

Once leukocytes (neutrophils and monocytes) have been recruited to a site of infection or cell death,
they must be activated to perform their functions. The responses of leukocytes consist of two sequential
sets of events: (1) recognition of the offending agents, which deliver signals that (2) activate the
leukocytes to ingest and destroy the offending agents and amplify the inflammatory reaction.
Leukocytes express several receptors that recognize external stimuli and deliver activating signals (Fig. 28).

Receptors for microbial products: Toll-like receptors (TLRs) recognize components of different types of
microbes.

G protein-coupled receptors found on neutrophils, macrophages, and most other types of leukocytes
recognize short bacterial peptides containing N-formylmethionyl residues.

Receptors for opsonins: Leukocytes express receptors for proteins that coat microbes. The process of
coating a particle, such as a microbe, to target it for ingestion (phagocytosis) is called opsonization, and
substances that do this are opsonins. These substances include antibodies, complement proteins, and
lectins. 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 Fc receptor
of phagocytes, called FcRI (Chapter 6). Components of the complement system, especially fragments of
the complement protein C3, are also potent opsonins, because these fragments bind to microbes and
phagocytes express a receptor, called the type 1 complement receptor (CR1), that recognizes
breakdown products of C3 (discussed later). Plasma lectins, mainly mannan-binding lectin, also bind to
bacteria and deliver them to leukocytes. The binding of opsonized particles to leukocyte Fc or C3
receptors promotes phagocytosis of the particles and activates the cells.

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- (IFN-), which is secreted by
natural killer cells reacting to microbes and by antigen-activated T lymphocytes during adaptive immune
responses (Chapter 6). IFN- 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.
Phagocytosis
Phagocytosis involves three sequential steps (Fig. 2-9): (1) recognition and attachment of the particle to
be ingested by the leukocyte; (2) its engulfment, with subsequent formation of a phagocytic vacuole;
and (3) killing or degradation of the ingested material.
Mannose receptors, scavenger receptors, and receptors for various opsonins all function to bind and
ingest microbes. The efficiency of phagocytosis is greatly enhanced when microbes are opsonized by
specific proteins (opsonins) for which the phagocytes express high-affinity receptors. As described
above, the major opsonins are IgG antibodies, the C3b breakdown product of complement, and certain
plasma lectins, notably mannan-binding lectin, all of which are recognized by specific receptors on
leukocytes.
Engulfment
After a particle is bound to phagocyte receptors, extensions of the cytoplasm (pseudopods) flow around
it, and the plasma membrane pinches off to form a vesicle (phagosome) that encloses the particle. The
phagosome then fuses with a lysosomal granule, resulting in discharge of the granule's contents into the

phagolysosome (see Fig. 2-9). During this process the phagocyte may also release granule contents into
the extracellular space.

Killing and Degradation

The final step in the elimination of infectious agents and necrotic cells is their killing and
degradation within neutrophils and macrophages, which occur most efficiently after activation of
the phagocytes. Microbial killing is accomplished largely by reactive oxygen species (ROS, also
called reactive oxygen intermediates) and reactive nitrogen species, mainly derived from NO.

The generation of ROS is due to the rapid assembly and activation of a multicomponent oxidase (NADPH
oxidase, also called phagocyte oxidase), which oxidizes NADPH (reduced nicotinamide-adenine
dinucleotide phosphate) and, in the process, reduces oxygen to superoxide anion. In neutrophils, this
rapid oxidative reaction is triggered by activating signals and accompanies phagocytosis, and is called
the respiratory burst.
Super oxide is then converted into hydrogen peroxide (H2O2), mostly by spontaneous dismutation. H2O2
is not able to efficiently kill microbes by itself. However, the azurophilic granules of neutrophils contain
the enzyme myeloperoxidase (MPO), which, in the presence of a halide such as Cl-, converts H2O2 to
hypochlorite (OCl, the active ingredient in household bleach). The latter is a potent antimicrobial agent
that destroys microbes by halogenation (in which the halide is bound covalently to cellular constituents)
or by oxidation of proteins and lipids (lipid peroxidation). The H2O2-MPO-halide system is the most
efficient bactericidal system of neutrophils. H2O2 is also converted to hydroxyl radical (OH), another
powerful destructive agent.
NO, produced from arginine by the action of nitric oxide synthase (NOS), also participates in microbial
killing.34 NO reacts with superoxide to generate the highly reactive free radical peroxynitrite (ONOO).
These oxygen- and nitrogen-derived free radicals attack and damage the lipids, proteins, and nucleic
acids of microbes as they do with host macromolecules.
Microbial killing can also occur through the action of other substances in leukocyte granules. Neutrophil
granules contain many enzymes, such as elastase, that contribute to microbial killing.35 Other
microbicidal granule contents include defensins, cationic arginine-rich granule peptides that are toxic to
microbes36; cathelicidins, antimicrobial proteins found in neutrophils and other cells37; lysozyme, which
hydrolyzes the muramic acid-N-acetylglucosamine bond, found in the glycopeptide coat of all bacteria;
lactoferrin, an iron-binding protein present in specific granules; major basic protein, a cationic protein of
eosinophils, which has limited bactericidal activity but is cytotoxic to many parasites; and
bactericidal/permeability increasing protein, which binds bacterial endotoxin and is believed to be
important in defense against some gram-negative bacteria.

Defects in Leukocyte Function

Because leukocytes play a central role in host defense, defects in leukocyte function, both inherited and
acquired, lead to increased vulnerability to infections.

Inherited defects in leukocyte adhesion.

Inherited defects in phagolysosome function. One such disorder is Chdiak-Higashi syndrome, an

autosomal recessive condition characterized by defective fusion of phagosomes and lysosomes in
phagocytes.

Inherited defects in microbicidal activity

Acquired deficiencies. Clinically, the most frequent cause of leukocyte defects is bone marrow
suppression, leading to decreased production of leukocytes.

TERMINATION OF THE ACUTE INFLAMMATORY RESPONSE

In part, inflammation declines simply because the mediators of inflammation are produced in rapid
bursts, only as long as the stimulus persists, have short half-lives, and are degraded after their release.
.Neutrophils also have short half-lives in tissues and die by apoptosis within a few hours after leaving the
blood. In addition, as inflammation develops the process also triggers a variety of stop signals that serve
to actively terminate the reaction.

Mediators of Inflammation
Mediators are generated either from cells or from plasma proteins. Cell-derived mediators are
normally sequestered in intracellular granules and can be rapidly secreted by granule exocytosis (e.g.,
histamine in mast cell granules) or are synthesized de novo (e.g., prostaglandins, cytokines) in response
to a stimulus. The major cell types that produce mediators of acute inflammation are platelets,
neutrophils, monocytes/macrophages, and mast cells, Plasma-derived mediators (e.g., complement
proteins, kinins) are produced mainly in the liver and present in the circulation as inactive precursors
that must be activated.
Active mediators are produced in response to various stimuli. These stimuli include microbial products,
substances released from necrotic cells, and 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. For instance, the cytokine TNF acts on
endothelial cells to stimulate the production of another cytokine, IL-1, and many chemokines.
Mediators vary in their range of cellular targets. They can act on one or a few target cell types, can
have diverse targets, or may even have differing effects on different types of cells.
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) or inhibited
(e.g., complement regulatory proteins break up and degrade activated complement components).

Table 2-4. The Actions of the Principal Mediators of Inflammation

Mediator
Principal Sources Actions
CELL-DERIVED
Histamine
Mast cells,
Vasodilation, increased vascular permeability,
basophils, platelets endothelial activation
Serotonin
Platelets
Vasodilation, increased vascular permeability
Prostaglandins
Mast cells,
Vasodilation, pain, fever
leukocytes
Leukotrienes
Mast cells,
Increased vascular permeability, chemotaxis, leukocyte
leukocytes
adhesion and activation
Platelet-activating Leukocytes, mast Vasodilation, increased vascular permeability,
factor
cells
leukocyte adhesion, chemotaxis, degranulation,
oxidative burst
Reactive oxygen
Leukocytes
Killing of microbes, tissue damage
species
Nitric oxide
Endothelium,
Vascular smooth muscle relaxation, killing of microbes
macrophages
Cytokines (TNF, Macrophages,
Local endothelial activation (expression of adhesion
IL-1)
endothelial cells,
molecules), fever/pain/anorexia/hypotension, decreased
mast cells
vascular resistance (shock)
Chemokines
Leukocytes,
Chemotaxis, leukocyte activation
activated
macrophages
PLASMA PROTEIN-DERIVED
Complement
Plasma (produced Leukocyte chemotaxis and activation, vasodilation
products (C5a, C3a, in liver)
(mast cell stimulation)
C4a)
Kinins
Plasma (produced Increased vascular permeability, smooth muscle
in liver)
contraction, vasodilation, pain
Proteases activated Plasma (produced Endothelial activation, leukocyte recruitment
during coagulation in liver)

CELL-DERIVED MEDIATORS

Vasoactive Amines: Histamine and Serotonin

The two major vasoactive amines, so named because they have important actions on blood vessels, are
histamine and serotonin. They are stored as preformed molecules in cells and are therefore among the

first mediators to be released during inflammation. The richest sources of histamine are the mast cells
that are normally present in the connective tissue adjacent to blood vessels. It is also found in blood
basophils and platelets.
Histamine is present in mast cell granules and is released by mast cell degranulation in response to a
variety of stimuli, including (1) physical injury such as trauma, cold, or heat; (2) binding of antibodies to
mast cells, which underlies allergic reactions (Chapter 6); (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).
Histamine causes dilation of arterioles and increases the permeability of venules. It is considered to be
the principal mediator of the immediate transient phase of increased vascular permeability, producing
interendothelial gaps in venules, as we have seen. Its vasoactive effects are mediated mainly via binding
to H1 receptors on microvascular endothelial cells.
Serotonin (5-hydroxytryptamine) is a preformed vasoactive mediator with actions similar to those of
histamine. It is present in platelets and certain neuroendocrine cells, e.g. in the gastrointestinal tract,
and in mast cells in rodents but not humans. Release of serotonin (and histamine) from platelets is
stimulated when platelets aggregate after contact with collagen, thrombin, adenosine diphosphate, and
antigen-antibody complexes. Thus, 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

When 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.

AA is a 20-carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid) that is derived

from dietary sources or by conversion from the essential fatty acid linoleic acid. It does not occur
free in the cell but is normally esterified in membrane phospholipids. Mechanical, chemical, and
physical stimuli or other mediators (e.g., C5a) release AA from membrane phospholipids
through the action of cellular phospholipases, mainly phospholipase A2.
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) (Fig. 2-11)
Prostaglandins (PGs) are produced by mast cells, macrophages, endothelial cells, and many other cell
types, and are involved in the vascular and systemic reactions of inflammation. They are produced by
the actions of two cyclooxgenases, the constitutively expressed COX-1 and the inducible enzyme COX-2.
The most important ones in inflammation are PGE2, PGD2, PGF2, PGI2 (prostacyclin), and TxA2
(thromboxane), each of which is derived by the action of a specific enzyme on an intermediate in the
pathway. Some of these enzymes have restricted tissue distribution. For example, platelets contain the
enzyme thromboxane synthetase, and hence TxA2 is the major product in these cells. Vascular
endothelium lacks thromboxane synthetase but possesses prostacyclin synthetase, which leads to the

formation of prostacyclin (PGI2). . Prostacyclin is a vasodilator, a potent inhibitor of platelet aggregation,

and also markedly potentiates the permeability-increasing and chemotactic effects of other mediators.
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. PGF2 stimulates the contraction of uterine and bronchial smooth muscle and small
arterioles, and PGD2 is a chemoattractant for neutrophils.
In addition to their local effects, the prostaglandins are involved in the pathogenesis of pain and fever in
inflammation. PGE2 is hyperalgesic and makes the skin hypersensitive to painful stimuli.
The lipoxygenase enzymes are responsible for the production of leukotrienes, which are secreted
mainly by leukocytes, are chemoattractants for leukocytes, and also have vascular effects. There are
three different lipoxygenases, 5-lipoxygenase being the predominant one in neutrophils. This enzyme
converts AA to 5-hydroxyeicosatetraenoic acid, which is chemotactic for neutrophils, and is 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. The
vascular leakage, as with histamine, is restricted to venules. Leukotrienes are much more potent than is
histamine in increasing vascular permeability and causing bronchospasm.
Lipoxins are also generated from AA by the lipoxygenase pathway, but unlike prostaglandins and
leukotrienes, the lipoxins are inhibitors of inflammation. The principal actions of lipoxins are to inhibit
leukocyte recruitment and the cellular components of inflammation. There is an inverse relationship
between the production of lipoxin and leukotrienes. lipoxins may be endogenous negative regulators of
leukotrienes and may thus play a role in the resolution of inflammation.

Table 2-5. Principal Inflammatory Actions of Arachidonic Acid Metabolites (Eicosanoids)

Action
Eicosanoid
Vasodilation
PGI2 (prostacyclin), PGE1, PGE2, PGD2
Vasoconstriction
Thromboxane A2, leukotrienes C4, D4, E4
Increased vascular permeability Leukotrienes C4, D4, E4
Chemotaxis, leukocyte adhesion Leukotriene B4, HETE
HETE, hydroxyeicosatetraenoic acid; PGI2, etc., prostaglandin I2, etc.
Many anti-inflammatory drugs work by inhibiting the synthesis of eicosanoids:
Cyclooxygenase inhibitors include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).
They inhibit both COX-1 and COX-2 and thus inhibit prostaglandin synthesis; aspirin does this by irreversibly
acetylating and inactivating cyclooxygenases. Selective COX-2 inhibitors are a newer class of these drugs.
Broad-spectrum inhibitors include corticosteroids. These powerful anti-inflammatory agents may act by reducing the
transcription of genes encoding COX-2, phospholipase A2, pro-inflammatory cytokines (such as IL-1 and TNF), and
iNOS.

Platelet-Activating Factor (PAF)

PAF is another phospholipid-derived mediator.54 Its name comes from its discovery as a factor that causes
platelet aggregation, but it is now known to have multiple inflammatory effects. A variety of cell types, including
platelets themselves, basophils, mast cells, neutrophils, macrophages, and endothelial cells, can elaborate PAF.
In addition to platelet aggregation, PAF causes vasoconstriction and bronchoconstriction, and at extremely low
concentrations it induces vasodilation and increased venular permeability.

Reactive Oxygen Species

Oxygen-derived free radicals may be released extracellularly from leukocytes after exposure to microbes, or
following a phagocytic challenge. Superoxide anion , hydrogen peroxide (H2O2), and hydroxyl radical (OH) are
the major species produced within cells, and can combine with NO to form reactive nitrogen species. As
mentioned earlier, the physiologic function of these ROS in leukocytes is to destroy phagocytosed microbes, but
release of these potent mediators can be damaging to the host (Chapter 1). They are implicated in the following
responses in inflammation:
Endothelial cell damage, with resultant increased vascular permeability.
Injury to other cell types (parenchymal cells, red blood cells).
Inactivation of antiproteases, such as 1-antitrypsin. This leads to unopposed protease activity, with increased
destruction of extracellular matrix.
Serum, tissue fluids, and host cells possess antioxidant mechanisms that protect against these potentially
harmful oxygen-derived radicals. These antioxidants were discussed in Chapter 1; they include (1) the enzyme
superoxide dismutase, which is found in or can be activated in a variety of cell types; (2) the enzyme catalase,
which detoxifies H2O2; (3) glutathione peroxidase, another powerful H2O2 detoxifier; (4) the copper-containing
serum protein ceruloplasmin; and (5) the iron-free fraction of serum transferrin. Thus, the influence of oxygenderived free radicals in any given inflammatory reaction depends on the balance between production and
inactivation of these metabolites by cells and tissues.

Nitric Oxide (NO)

NO is a soluble gas that is produced not only by endothelial cells but also by macrophages and some neurons in
the brain. It acts in a paracrine manner on target cells. 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) (Fig. 2-12). 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. NO reduces platelet aggregation and adhesion.

Cytokines and Chemokines

Cytokines are proteins produced by many cell types (principally activated lymphocytes and macrophages, but
also endothelial, epithelial, and connective tissue cells) that modulate the functions of other cell types.
Chemokines are a family of small (8 to 10 kD) proteins that act primarily as chemoattractants for specific types
of leukocytes.

Table 2-6. Cytokines in Inflammation

Cytokine Principal Sources

Principal Actions in Inflammation

IN ACUTE INFLAMMATION

TNF

Macrophages, mast cells, T

lymphocytes

Stimulates expression of endothelial adhesion

molecules and secretion of other cytokines;
systemic effects
IL-1
Macrophages, endothelial cells, some Similar to TNF; greater role in fever
epithelial cells
IL-6
Macrophages, other cells
Systemic effects (acute-phase response)
Chemokines Macrophages, endothelial cells, T
Recruitment of leukocytes to sites of inflammation;
lymphocytes, mast cells, other cell
migration of cells to normal tissues
types
IN CHRONIC INFLAMMATION

IL-12
IFN-

Dendritic cells, macrophages

T lymphocytes, NK cells

IL-17

T lymphocytes

Increased production of IFN-

Activation of macrophages (increased ability to kill
microbes and tumor cells)
Recruitment of neutrophils and monocytes

IFN-, interferon-; IL-1, interleukin-1; NK cells, natural killer cells; TNF, tumor necrosis
factor.
The most important cytokines involved in inflammatory reactions are listed. Many other
cytokines may play lesser roles in inflammation. There is also considerable overlap between
the cytokines involved in acute and chronic inflammation. Specifically, all the cytokines listed
under acute inflammation may also contribute to chronic inflammatory reactions.

Lysosomal Constituents of Leukocytes

Neutrophils and monocytes contain lysosomal granules, which, when released, may contribute to the
inflammatory response. Neutrophils have two main types of granules. The smaller specific (or secondary)
granules contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline
phosphatase. The larger azurophil (or primary) granules contain myeloperoxidase, bactericidal factors (lysozyme,
defensins), acid hydrolases, and a variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases,
proteinase 3).40 Both types of granules can fuse with phagocytic vacuoles containing engulfed material, or the
granule contents can be released into the extracellular space.
Because of the destructive effects of lysosomal enzymes, the initial leukocytic infiltration, if unchecked, can
potentiate further inflammation and tissue damage. These harmful proteases, however, are held in check by a
system of antiproteases in the serum and tissue fluids.

Neuropeptides
Neuropeptides are secreted by sensory nerves and various leukocytes, and play a role in the initiation and
propagation of an inflammatory response. 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

A variety of phenomena in the inflammatory response are mediated by plasma proteins that belong to three
interrelated systems: the complement, kinin, and clotting systems.

Complement System
Complement proteins are present in inactive forms in the plasma, and many of them are activated to become
proteolytic enzymes that degrade other complement proteins, thus forming an enzymatic cascade capable of
tremendous amplification. The critical step in complement activation is the proteolysis of the third (and most
abundant) component, C3. Cleavage of C3 can occur by one of three pathways: the classical pathway, which is
triggered by fixation of C1 to antibody (IgM or IgG) that has combined with antigen; the alternative pathway,
which can be triggered by microbial surface molecules (e.g., endotoxin, or LPS), complex polysaccharides, cobra
venom, and other substances, in the absence of antibody; and the lectin pathway, in which plasma mannosebinding lectin binds to carbohydrates on microbes and directly activates C1. Whichever pathway is involved in
the early steps of complement activation, they all 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).
The biologic functions of the complement system fall into three general categories (see Fig. 2-14):

Inflammation. C3a, C5a, and, to a lesser extent, C4a are cleavage products of the corresponding
complement components that stimulate histamine release from mast cells and thereby increase
vascular permeability and cause vasodilation. They are called anaphylatoxins because they have effects
similar to those of mast cell mediators that are involved in the reaction called anaphylaxis (Chapter 6).
C5a is also a powerful chemotactic agent for neutrophils, monocytes, eosinophils, and basophils. In
addition, C5a activates the lipoxygenase pathway of AA metabolism in neutrophils and monocytes,
causing further release of inflammatory mediators.
Phagocytosis. C3b and its cleavage product iC3b (inactive C3b), when fixed to a microbial cell wall, act as
opsonins and promote phagocytosis by neutrophils and macrophages, which bear cell surface receptors
for the complement fragments.
Cell lysis. The deposition of the MAC on cells makes these cells permeable to water and ions and results
in death (lysis) of the cells.

Among the complement components, C3a and C5a are the most important inflammatory mediators.

Coagulation and Kinin Systems

Inflammation and blood clotting are often intertwined, with each promoting the other.74 The clotting system is
divided into two pathways that converge, culminating in the activation of thrombin and the formation of fibrin
(Fig. 2-15) (Chapter 4). The intrinsic clotting pathway is a series of plasma proteins that can be activated by
Hageman factor (factor XII), a protein synthesized by the liver that circulates in an inactive form. Factor XII is
activated upon contact with negatively charged surfaces, for instance 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.
inflammation increases the production of several coagulation factors, makes the endothelial surface prothrombogenic, and inhibits anticoagulation mechanisms, thus promoting clotting. Conversely, thrombin, a
product of clotting, promotes inflammation.
Kinins are vasoactive peptides derived from plasma proteins, called kininogens, by the action of specific
proteases called kallikreins. The kinin and coagulation systems are also intimately connected.
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.

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

Role in Inflammation
Mediators
Prostaglandins
Vasodilation
Nitric oxide
Histamine
Histamine and serotonin
Increased vascular permeability
C3a and C5a (by liberating vasoactive amines from mast
cells, other cells)
Bradykinin
Leukotrienes C4, D4, E4
PAF
Substance P
Chemotaxis, leukocyte recruitment and TNF, IL-1
Chemokines
activation
C3a, C5a
Leukotriene B4
(Bacterial products, e.g., N-formyl methyl peptides)
IL-1, TNF
Fever
Prostaglandins
Prostaglandins
Pain
Bradykinin
Lysosomal enzymes of leukocytes
Tissue damage
Reactive oxygen species
Nitric oxide

Outcomes of Acute Inflammation

all acute inflammatory reactions may have one of three outcomes (Fig. 2-16):

Complete resolution. In a perfect world, all inflammatory reactions, once they have succeeded in
neutralizing and eliminating the injurious stimulus, should end with restoration of the site of acute
inflammation to normal. This is called resolution and is the usual outcome when the injury is limited or
short-lived or when there has been little tissue destruction and the damaged parenchymal cells can
regenerate. Resolution involves removal of cellular debris and microbes by macrophages, and resorption
of edema fluid by lymphatics.
Healing by connective tissue replacement (fibrosis). This occurs after substantial tissue destruction, when
the inflammatory injury involves tissues that are incapable of regeneration, or when there is abundant
fibrin exudation in tissue or serous cavities (pleura, peritoneum) that cannot be adequately cleared. In
all these situations, connective tissue grows into the area of damage or exudate, converting it into a
mass of fibrous tissue-a process also called organization.

Progression of the response to chronic inflammation (discussed below). This may follow acute inflammation,
or the response may be chronic from the onset. Acute to chronic transition occurs when the acute inflammatory
response cannot be resolved, as a result of either the persistence of the injurious agent or some interference
with the normal process of healing.79 For example, bacterial infection of the lung may begin as a focus of acute
inflammation (pneumonia), but its failure to resolve may lead to extensive tissue destruction and formation of a
cavity in which the inflammation continues to smolder, leading eventually to a chronic lung abscess.

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 (Fig. 2-17). The importance of
recognizing the gross and microscopic patterns is that they often provide valuable clues about the underlying
cause.

SEROUS INFLAMMATION
Serous inflammation is 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 (Fig. 2-18).

FIBRINOUS INFLAMMATION
A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges,
pericardium (Fig. 2-19A) and pleura. 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

This type of inflammation is characterized by the production of large amounts of pus or purulent exudate
consisting of neutrophils, liquefactive necrosis, and edema fluid. Certain bacteria (e.g., staphylococci) produce
this localized suppuration and are therefore referred to as pyogenic (pus-producing) bacteria. A common
example of an acute suppurative inflammation is acute appendicitis. Abscesses are localized collections of
purulent inflammatory tissue caused by suppuration buried in a tissue, an organ, or a confined space.

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 (Fig. 2-21). Ulceration can occur only when tissue necrosis and resultant
inflammation exist on or near a surface. Ulcerations are best exemplified by peptic ulcer of the stomach or
duodenum, in which acute and chronic inflammation coexist.

Summary of Acute Inflammation

When a host encounters an injurious agent, such as an infectious microbe or dead cells, phagocytes that reside
in all tissues try to eliminate these agents. At the same time phagocytes and other host cells react to the
presence of the foreign or abnormal substance by liberating cytokines, lipid messengers, and other mediators of
inflammation. Some of these mediators act on small blood vessels in the vicinity and promote the efflux of
plasma and the recruitment of circulating leukocytes to the site where the offending agent is located. The
recruited leukocytes are activated by the injurious agent and by locally produced mediators, and the activated
leukocytes try to remove the offending agent by phagocytosis. As the injurious agent is eliminated and antiinflammatory mechanisms become active, the process subsides and the host returns to a normal state of health.
If the injurious agent cannot be quickly eliminated, the result may be chronic inflammation.

The clinical and pathologic manifestations of the inflammatory response are caused by several reactions.
The vascular phenomena of acute inflammation are characterized by 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. Plasma proteins leave the vessels, most commonly through widened
interendothelial cell junctions of the venules. The redness (rubor), warmth (calor), and swelling (tumor)
of acute inflammation are caused by the increased blood flow and edema. 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 that
are activated by the offending agent and by endogenous mediators 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
Chronic inflammation is inflammation of prolonged duration (weeks or months) in which inflammation, tissue
injury, and attempts at repair coexist, in varying combinations. It may follow acute inflammation, as described
earlier, or chronic inflammation may begin insidiously, as a low-grade, smoldering response without any
manifestations of an acute reaction.

CAUSES OF CHRONIC INFLAMMATION

Chronic inflammation arises in the following settings:

Persistent infections by microorganisms that are difficult to eradicate, such as mycobacteria, and certain
viruses, fungi, and parasites. These organisms often evoke an immune reaction called delayed-type
hypersensitivity (Chapter 6). The inflammatory response sometimes takes a specific pattern called a
granulomatous reaction.
Immune-mediated inflammatory diseases. Chronic inflammation plays an important role in a group of
diseases that are caused by excessive and inappropriate activation of the immune system.
Prolonged exposure to potentially toxic agents, either exogenous or endogenous. An example of an exogenous
agent is particulate silica.

MORPHOLOGIC FEATURES
In contrast to acute inflammation, which is manifested by vascular changes, edema, and predominantly
neutrophilic infiltration, chronic inflammation is characterized by:

Infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells (Fig. 222)
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. The mononuclear phagocyte system
(sometimes called reticuloendothelial system) consists of closely related cells of bone marrow origin, including
blood monocytes and tissue macrophages. The latter are diffusely scattered in the connective tissue or located
in organs such as the liver (Kupffer cells), spleen and lymph nodes (sinus histiocytes), lungs (alveolar
macrophages), and central nervous system (microglia). Mononuclear phagocytes arise from a common
precursor in the bone marrow, which gives rise to blood monocytes. From the blood, monocytes migrate into
various tissues and differentiate into macrophages. The half-life of blood monocytes is about 1 day, whereas the
life span of tissue macrophages is several months or years. When a monocyte reaches the extravascular tissue, it
undergoes transformation into a larger phagocytic cell, the macrophage. Macrophages may be activated by a
variety of stimuli, including microbial products that engage TLRs and other cellular receptors, cytokines (e.g.,
IFN-) secreted by sensitized T lymphocytes and by natural killer cells, and other chemical mediators (Fig. 2-24).
The products of activated macrophages serve to eliminate injurious agents such as microbes and to initiate the
process of repair, and are responsible for much of the tissue injury in chronic inflammation. Activation of
macrophages results in increased levels of lysosomal enzymes and reactive oxygen and nitrogen species, and
production of cytokines, growth factors, and other mediators of inflammation. Some of these products are toxic
to microbes and host cells (e.g., reactive oxygen and nitrogen species) or to extracellular matrix (proteases);
some cause influx of other cell types (e.g., cytokines, chemotactic factors); and still others cause fibroblast
proliferation, collagen deposition, and angiogenesis (e.g., growth factors). As illustrated in Fig. 2-10, different
macrophage populations may serve distinct functions-some may be important for microbial killing and

inflammation, and others for repair.

tissue destruction is one of the hallmarks of chronic inflammation.

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

Other cell types involved in chronic inflammation include lymphocytes, plasma cells, eosinophils, and mast cells.
Lymphocytes and macrophages interact in a bidirectional way, and these reactions play an important role in
chronic inflammation (Fig. 2-25). Macrophages display antigens to T cells and produce membrane molecules
(costimulators) and cytokines (notably IL-12) that stimulate T-cell responses (Chapter 6). Activated T
lymphocytes produce cytokines, some of which recruit monocytes from the circulation and one, IFN-, is a
powerful activator of macrophages.
Plasma cells develop from activated B lymphocytes and produce antibodies directed either against persistent
foreign or self antigens in the inflammatory site or against altered tissue components.
Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections (Fig. 2-26). 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.
Mast cells are widely distributed in connective tissues and participate in both acute and chronic inflammatory
reactions. Mast cells express on their surface the receptor (FcRI) 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 (Chapter 6).
Although neutrophils are characteristic of acute inflammation, many forms of chronic inflammation, lasting for
months, continue to show large numbers of neutrophils, In chronic bacterial infection of bone (osteomyelitis), a
neutrophilic exudate can persist for many months.

GRANULOMATOUS INFLAMMATION
Granulomatous inflammation is a distinctive pattern of chronic inflammation that is encountered in a limited
number of infectious and some noninfectious conditions. Briefly, a granuloma is a cellular attempt to contain an
offending agent that is difficult to eradicate. In this attempt there is often strong activation of T lymphocytes
leading to macrophage activation, which can cause injury to normal tissues. Tuberculosis is the prototype of the
granulomatous diseases, but sarcoidosis, cat-scratch disease, lymphogranuloma inguinale, leprosy, brucellosis,
syphilis, some mycotic infections, berylliosis, reactions of irritant lipids, and some autoimmune diseases are also
included.
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.
Frequently, epithelioid cells fuse to form giant cells in the periphery or sometimes in the center of granulomas.
here are two types of granulomas, which differ in their pathogenesis. Foreign body granulomas are incited by
relatively inert foreign bodies. Typically, foreign body granulomas form around material such as talc (associated
with intravenous drug abuse) (Chapter 9), sutures, or other fibers that are large enough to preclude
phagocytosis by a single macrophage and do not incite any specific inflammatory or immune response.
Immune granulomas are caused by a variety of agents that are capable of inducing a cell-mediated immune
response (Chapter 6). This type of immune response produces granulomas usually when the inciting agent is
poorly degradable or particulate. In such responses macrophages engulf foreign protein antigen, process it, and
present peptides to antigen-specific T lymphocytes, causing their activation (Chapter 6). The responding T cells
produce cytokines, such as IL-2, which activates other T cells, perpetuating the response, and IFN-, which is
important in activating macrophages and transforming them into epithelioid cells and multinucleate giant cells.
The prototype of the immune granuloma is that caused by infection with Mycobacterium tuberculosis. In this
disease the granuloma is referred to as a tubercle. It is often characterized by the presence of central caseous
necrosis (see Fig. 2-27). In contrast, caseous necrosis is rare in other granulomatous diseases.

Table 2-8. Examples of Diseases with Granulomatous Inflammation

Disease
Cause
Tissue Reaction
Tuberculosis
Mycobacterium
Caseating granuloma (tubercle): focus of activated
tuberculosis
macrophages (epithelioid cells), rimmed by fibroblasts,
lymphocytes, histiocytes, occasional Langhans giant cells;
central necrosis with amorphous granular debris; acid-fast
bacilli
Leprosy
Mycobacterium leprae Acid-fast bacilli in macrophages; noncaseating
granulomas
Syphilis
Treponema pallidum Gumma: microscopic to grossly visible lesion, enclosing
wall of histiocytes; plasma cell infiltrate; central cells
necrotic without loss of cellular outline
Cat-scratch disease Gram-negative bacillus Rounded or stellate granuloma containing central granular
debris and recognizable neutrophils; giant cells uncommon
Sarcoidosis
Unknown etiology
Noncaseating granulomas with abundant activated
macrophages
Crohn disease
Immune reaction
Occasional noncaseating granulomas in the wall of the
(inflammatory
against intestinal
intestine, with dense chronic inflammatory infiltrate
bowel disease)
bacteria, self-antigens

Systemic Effects of Inflammation

The systemic changes associated with acute inflammation are collectively called the acute-phase response, or
the systemic inflammatory response syndrome.
Fever, characterized by an elevation of body temperature, usually by 1 to 4C, is one of the most prominent
manifestations of the acute-phase response, especially when inflammation is associated with infection. Fever is
produced in response to substances called pyrogens that act by stimulating prostaglandin synthesis in the
vascular and perivascular cells of the hypothalamus. Bacterial products, such as LPS (called exogenous pyrogens),
stimulate leukocytes to release cytokines such as IL-1 and TNF (called endogenous pyrogens) that increase the
enzymes (cyclooxygenases) that convert AA into prostaglandins.84 In the hypothalamus, the prostaglandins,
especially PGE2reset the temperature set point at a higher level. NSAIDs, including aspirin, reduce fever by
inhibiting prostaglandin synthesis.
Acute-phase proteins are plasma proteins, mostly synthesized in the liver, whose plasma concentrations may
increase several hundred-fold as part of the response to inflammatory stimuli.85 Three of the best-known of
these proteins are C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein. Synthesis of these
molecules by hepatocytes is up-regulated by cytokines, especially IL-6 (for CRP and fibrinogen) and IL-1 or TNF
(for SAA).
Leukocytosis is a common feature of inflammatory reactions, especially those induced by bacterial infections.
The leukocytosis occurs initially because of accelerated release of cells from the bone marrow postmitotic
reserve pool (caused by cytokines, including TNF and IL-1). Most bacterial infections induce an increase in the
blood neutrophil count, called neutrophilia. Viral infections, such as infectious mononucleosis, mumps, and
German measles, cause an absolute increase in the number of lymphocytes (lymphocytosis). In bronchial
asthma, allergy, and parasitic infestations, there is an increase in the absolute number of eosinophils, creating
an eosinophilia.
Other manifestations of the acute-phase response include 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.
In severe bacterial infections (sepsis) the 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 manifestations such as disseminated intravascular coagulation, cardiovascular failure, and
metabolic disturbance, which are described as septic shock.

Consequences of Defective or Excessive Inflammation

Defective inflammation typically results in increased susceptibility to infections, because the inflammatory
response is a central component of the early defense mechanisms that immunologists call innate immunity
(Chapter 6). It is also associated with delayed wound healing, because inflammation is essential for clearing
damaged tissues and debris, and provides the necessary stimulus to get the repair process started.
Excessive inflammation is the basis of many types of human disease. Allergies, in which individuals mount
unregulated immune responses against commonly encountered environmental antigens, and autoimmune
diseases, in which immune responses develop against normally tolerated self-antigens, are disorders in which
the fundamental cause of tissue injury is inflammation .