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CHAPTER THREE
INFLAMMATION
General Features
Inflammation is defined as "the response of living vascularized tissues to harmful agents.” It consists
principally of vascular changes associated with leukocytes infiltration and systemic reactions." Inflammation
is a fundamental and common pathologic process seen in many disease states. It is essentially a protective
response, the aim of which is to get rid of the injurious agents (e.g., microbes, toxins) as well as its
consequences (e.g., necrotic cells and tissues). Inflammation is concurrently tangled with another process
(repair) that tries to mend the damaged tissues resulting from the battle between the offending agent and the
host. Without inflammation, infections would go uninhibited, wounds would never heal, and injured organs
might remain permanently damaged. Some times, however, inflammation and its associated repair may be
potentially harmful. For this reason, pharmacies flourish with anti-inflammatory drugs, which ideally control
the harmful sequelae of inflammation yet do not interfere with its beneficial effects.
Many tissues and cells are involved in the inflammatory reaction, including plasma fluid proteins,
circulating leukocytes, blood vessels, and cellular and extracellular constituents of connective tissues. The
circulating leukocytes include neutrophils, monocytes, eosinophils, lymphocytes, basophils, in addition to
platelets. The connective tissue cells are mast cells, fibroblasts, macrophages, and lymphocytes. The
extracellular matrix consists of structural proteins (collagen, elastin), adhesive glycoproteins (fibronectin,
laminin), and proteoglycans.
Inflammation is divided into acute or chronic. The latter includes also a specific form called granulomatous
inflammation.
Acute inflammation is rapid in onset (seconds or minutes), of relatively short duration (minutes, hours, or
at most a few days), characterized by the exudation of fluid and plasma proteins, & the emigration of
leukocytes, predominantly neutrophils.
Chronic inflammation, in contradistinction, is of insidious onset, of longer duration, and is associated
histologically with the presence of lymphocytes, macrophages, plasma cells, proliferation of blood vessels
and fibroblasts.
In both forms tissue necrosis of varying extent occurs. The vascular and cellular reactions of both acute and
chronic inflammation are mediated by chemical substances (chemical mediators) that are derived from
plasma proteins or cells. Such substances, acting singly, in combinations, or in sequence, amplify the
inflammatory response and influence its evolution.
The five cardinal signs of inflammation are rubor (redness), tumor (swelling), calor (heat), dolor (pain),
and loss of function (functio laesa). The first four signs are typically more prominent in acute inflammations
than in chronic ones.
ACUTE INFLAMMATION
Stimuli of acute inflammation
Acute inflammatory reactions are triggered by a variety of stimuli that include
1. Infections: bacterial, viral, parasitic and microbial toxins
2. Physical and chemical agents (trauma, thermal injuries, irradiation, toxins, strong acids, etc.)
3. Tissue necrosis (of any from or cause)
4. Foreign bodies (splinters, dirt, sutures)
5. Immune reactions (hypersensitivity and autoimmune reactions)
Exudation is the escape of fluid, proteins, and blood cells from the vascular system into the interstitial
tissue. An exudate is an extravascular fluid that has a high protein concentration and a specific gravity above
1.020. It involves significant alteration in the normal permeability of small blood vessels in the area of
injury. In contrast, a transudate is a fluid with low protein content (most of which is albumin) and a specific
gravity of less than 1.012
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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. Edema refers to an excess of fluid in the interstitial
tissues or body cavities; the accumulated fluid can be either an exudate or a transudate. Pus (purulent
exudate) is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells and, in
many cases, microbes (pyogenic bacteria).
Acute inflammation has three major components: (Fig. 3-1)
A. Vasodilation associated with increased blood flow
B. Increased vascular permeability associated with decreased blood flow
C. Emigration and activation of leukocytes and phagocytosis
A. Vasodilation and increased blood flow
This is, sometimes, preceded by a transient constriction of arterioles, lasting a few seconds. Vasodilation
first involves the arterioles, which leads to an increase in blood flow; this in turn leads to opening of new
capillary beds in the area with subsequent dilation of capillaries & venules. This process allows more blood
to flow into the area, a process known as “active hyperemia” (hyper- = increased; -emia = blood). These
changes explain the clinically noted heat and redness. Vasodilation is induced by the action of several
mediators (such as histamine) on vascular smooth muscles. It is possible that autonomic nerve impulses may
also play a role in relaxation of arteriolar smooth muscle leading to their dilation.
B. Increased Vascular Permeability and decreased blood flow
Increased vascular permeability leads to the escape of exudates into the extravascular tissue. This is driven
by the increased hydrostatic pressure owing to increased blood flow through the dilated vessels and is
perpetuated through the loss of proteins from the plasma that reduces the intravascular osmotic pressure and
increases the osmotic pressure of the interstitial fluid.
Several mechanisms have been proposed for the increased vascular permeability, that include
1. Formation of endothelial gaps in venules due to endothelial cells contraction. This is the most common
mechanism & is elicited by several mediators e.g. histamine, bradykinin, and leukotrienes. Binding of these
mediators to receptors on endothelial cells leads to stimulation of contractile proteins (such as myosin). The
result is contraction of the endothelial cells and separation of intercellular junctions that eventuate in
intercellular gaps formation.
2. Junctional retraction caused by chemical mediators such as TNF and IL-1; these induce structural
reorganization of the cytoskeleton of the cells.
3. Direct endothelial cell injury as by burns or infections. Because of endothelial damage and exposure of
the subendothelial thrombogenic collagen, this type is frequently associated with platelets adhesion with
subsequent thrombosis.
4. Leukocyte-dependant injury due to accumulation of leukocytes and their activation products (such as
toxic oxygen radicals and proteolytic enzymes) during the inflammatory response. These lead to endothelial
cell damage.
According to the above mechanisms, there are three basic patterns of increased permeability
1. Immediate transient response lasting for 30 minutes or less, mediated mainly by the actions of histamine
and leukotrienes on endothelium
2. Delayed response starting at about 2 hours and lasting for about 8 hours, mediated principally by kinins,
complement products.
3. Prolonged response that is most noticeable after direct endothelial injury, e.g. after burns.
The inflammatory exudate, in addition to leukocytes, is composed of plasma proteins; of these, two play a
particularly important role
1. Immunoglobulins; a group of antibodies that have the ability to react with certain antigens, making them
vulnerable to the actions of neutrophils and macrophages (opsonization)
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1. Binding of leukocytes to the endothelial cells. Normally, the vascular endothelium does not bind circulating
cells or impede their passage. In inflammation, however, the endothelium becomes activated to permit binding
of leukocytes to its surface. This is followed by
2. Transmigration of leukocytes across the endothelium (diapedesis)
3. Migration of leukocytes within the interstitial tissues toward the focus of tissue injury.
Because blood flow slows down in inflammation, more white cells assume a peripheral position along the
endothelial surface. This process is called margination. Subsequently, leukocytes tumble and roll over slowly
along the endothelium and eventually come to rest through firm adhesions with the endothelial cells. In time,
the endothelium becomes virtually lined by white cells, an appearance called pavementing. After firm adhesion,
leukocytes insert pseudopods into the junctions between the endothelial cells, squeeze through interendothelial
junctions, and eventually, traverse the basement membrane and escape into the extravascular space.
Neutrophils, monocytes, lymphocytes, eosinophils, and basophils, all use the same pathway to migrate from the
blood into tissues. Leukocyte adhesion and transmigration are achieved by the binding of complementary
adhesion molecules on the leukocyte and endothelial surfaces, a process regulated by chemical mediators. The
adhesion receptors involved belong to several molecular families including selectins and integrins. The next
step in the process is migration of the leukocytes through the endothelium, called transmigration or diapedesis.
Chemokines (chemoattractants) act on the adherent leukocytes and stimulate the cells to migrate toward the site
of injury or infection. Certain adhesion molecules, present in the intercellular junction of endothelium, are
involved in the migration of leukocytes. Leukocyte diapedesis, similar to increased vascular permeability,
occurs predominantly in the venules. After traversing the endothelium, leukocytes eventually pierce the
basement membrane, probably by secreting degrading enzymes such as collagenases & elastases. Once
leukocytes enter the extravascular connective tissue, they are able to adhere to the extracellular matrix by virtue
of integrins and CD44. Thus, the leukocytes are retained at the site where they are needed. (Fig. 3-3) The type
of emigrating leukocyte varies with the age of the inflammatory response and with the type of stimulus. In most
forms of acute inflammation, neutrophils predominate in the inflammatory infiltrate during the first 6 to 24
hours, and then are replaced by monocytes in 24 to 48 hours. After entering tissues, neutrophils are short-lived;
they undergo apoptosis (self destruction) and disappear after 24 to 48 hours, whereas monocytes (by now called
macrophages: macro- = large and phage = eater) survive longer and thus outlive neutrophils and become more
apparent. There are, however, exceptions to this pattern of cellular exudation. In certain infections—for
example, those produced by Pseudomonas organisms—neutrophils predominate over 2 to 4 days; in viral
infections, lymphocytes may be the first cells to arrive; in some hypersensitivity reactions and parasitic
infestations, eosinophils may be the main cell type.
Chemotaxis
After extravasation, leukocytes emigrate in tissues toward the site of injury; this is achieved by a process called
chemotaxis. Chemotaxis is defined as locomotion oriented along a chemical gradient of chemoattractants. All
granulocytes, monocytes and, to a lesser extent, lymphocytes respond to chemoattractants (chemotactic stimuli)
with varying rates of speed. Both exogenous and endogenous substances can act as chemoattractants. The
former is exemplified by bacterial products. Endogenous chemoattractants, however, include several
chemical mediators:
1. Components of the complement system, particularly C5a
2. Products of the lipoxygenase pathway, mainly leukotriene B4 (LTB4)
3. Cytokines (secreted from cells) e.g., IL-8
All the chemoattractants mentioned above bind to specific receptors on the surface of leukocytes. Signals
initiated from these receptors result in recruitment & activation of specific leukocytic proteins including
tyrosine kinases. These changes eventuate in polymerization of actin that results in increased amounts of this
contractile protein at the leading edge of the cell. The leukocyte moves by extending filopodia that pull the back
of the cell in the direction of extension, much as a car with front-wheel drive is pulled by the wheels in front.
Leukocyte Activation
This refers to induction of a number of responses within leukocytes, which are mediated by microbes, products
of necrotic cells, antigen-antibody complexes, and cytokines. These mediators trigger several signaling
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pathways in leukocytes that result in an increase in cytoplasmic Ca
++
and activation of enzymes. The activation
of leukocytes is reflected functionally as follows:
1. Production of arachidonic acid (AA) metabolites
2. Secretion of lysosomal enzymes and other microbicidal substances
3. Modulation of leukocyte adhesion molecules allowing firm adhesion to endothelium
4. Activation of macrophages: through the release of IFN-γ (major macrophage-activating cytokine), which is
secreted by natural killer (NK) cells.
5. Activation of phagocytosis through stimulation of opsonins-receptors. The process of coating a particle, such
as a microbe, to make it vulnerable for phagocytosis is called opsonization; substances that do this are opsonins.
Phagocytosis (Fig. 3-4)
Phagocytosis is one of the major functions of the accumulated neutrophils and macrophages at the inflammatory
focus, being responsible for eliminating the injurious agents.
Phagocytosis involves three distinct but interrelated steps:
1. Recognition and attachment of the particle to be ingested by the leukocyte
2. Its engulfment, with subsequent formation of a phagocytic vacuole
3. Killing and degradation of the ingested material.
Recognition and Attachment
Although neutrophils and macrophages can engulf bacteria without attachment to specific receptors, typically
the phagocytosis of microbes and dead cells is initiated by recognition of these particles by receptors expressed
on the leukocyte surface. The efficiency of phagocytosis is greatly enhanced when microbes are opsonized by
specific proteins (opsonins) for which the phagocytes express high-affinity receptors. The major opsonins are
IgG antibodies, the C3b breakdown product of complement, and certain plasma lectins.
Engulfment
Binding of a particle to phagocytic leukocyte receptors initiates the process of active phagocytosis.
During engulfment, extensions of the cytoplasm (pseudopods) flow around the particle to be engulfed,
eventually resulting in complete enclosure of the particle within a phagosome created by the plasma membrane
of the cell. The limiting membrane of this phagocytic vacuole then fuses with the limiting membrane of a
lysosomal granule forming phagolysosome. This fusion results in discharge of lysosomal contents into the
phagolysosome.
Killing and Degradation
The ultimate 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 these phagocytes.
Microbial
killing is accomplished largely by oxygen-dependent mechanisms, which depends on the production of reactive
oxygen species,
particularly H2O2. The latter is generally not able to efficiently kill microbes by itself.
However, the azurophilic granules of neutrophils contain the enzyme myeloperoxidase (MPO), which, in the
presence of Cl
-
, converts H2O2 to hypochlorite (HOCl). The latter is a potent antimicrobial agent that destroys
microbes by halogenation or by oxidation of proteins and lipids (lipid peroxidation). The H2O2-MPO-halide
system is the most efficient bactericidal system in neutrophils. Oxygen-independent degradation depends on the
release of granules, containing proteolytic enzymes such as defensins (antibacterial peptide attacking bacterial
cell membrane), proteolytic enzymes such as elastases, lysozymes, and cationic proteins. The major basic
protein of eosinophils has limited bactericidal activity but is cytotoxic to many parasites. After killing, acid
hydrolases, which are normally stored in lysosomes, degrade the microbes within phagolysosomes.
Macrophages are excellent phagocytes and are particularly good at engulfing and processing antigenic
substances and presenting altered antigens to other cells (lymphocytes) for ultimate destruction.
Release of leukocyte products and leukocyte-induced Tissue Injury
During activation and phagocytosis, leukocytes 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, reactive oxygen radicals, and products of AA metabolism (including prostaglandins and leukotrienes).
These products are capable of causing injuries of the host endothelium and tissues, and may thus amplify the
effects of the initial injurious agent. Products of monocytes/macrophages and other leukocyte types have
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additional potentially harmful products (see chronic inflammation). Thus, if persistent and unchecked, the
leukocyte infiltrate itself becomes harmful. Leukocyte-dependent tissue injury underlies many acute and
chronic human diseases as listed in the following table
Clinical Examples of Leukocyte-Induced Injury
Acute
Chronic
Acute respiratory distress syndrome Arthritis
Acute transplant rejection
Asthma
Asthma
Atherosclerosis
Glomerulonephritis
Chronic lung disease
Reperfusion injury
Chronic rejection
Septic shock
Vasculitis
Defects in Leukocyte Function
Leukocytes play a central role in host defense. Not surprisingly, therefore, defects in leukocyte function, genetic
or acquired, lead to increased vulnerability to infections. Impairments of virtually every phase of leukocyte
function—from adherence to vascular endothelium to microbicidal activity—have been identified, and the
existence of clinical genetic deficiencies in each step in the process has been described. These defects are
manifested clinically by recurrent bacterial infections and impaired wound healing. In practice, the most
frequent cause of leukocyte defects is bone marrow suppression, leading to reduced production of leukocytes.
This is seen following therapies for cancer (radiation and chemotherapy) and when the marrow space is
replaced and destroyed by metastatic cancers to bone.
Contribution of tissue cells to the inflammatory process
There are in addition to leukocytes other cells that are resident in tissues. These also serve important functions
in initiating acute inflammation. The two most important of these cell types are mast cells and tissue
macrophages. Mast cells react to physical trauma, breakdown products of complement, microbial products, etc.
The cells release histamine, leukotrienes, enzymes, and many cytokines (including TNF, IL-1, and
chemokines), all of which contribute to inflammation. Macrophages recognize microbial products and secrete
most of the cytokines important in acute inflammation. These cells are stationed in tissues to rapidly recognize
potentially injurious stimuli and initiate the host defense reaction.
CHEMICAL MEDIATORS OF INFLAMMATION
Chemical mediators are substances that are responsible for many of the inflammatory events. According to their
origin, they are either
1. Plasma-derived (e.g. complements & kinins): these are present in plasma in precursor forms and need to be
activated to function.
2. Cell-derived: either
a. ready-made within intracellular granules (e.g., histamine in mast cell granules) or
b. synthesized when needed (e.g., prostaglandins, cytokines) in response to a stimulus.
The major cellular sources are platelets, neutrophils, monocytes/macrophages, and mast cells. Most mediators
perform their job by binding to specific receptors on target cells. Most mediators have the potential to cause
harmful effects that is why their biological actions are short-lived or they are inactivated or degraded rapidly by
other substances. One mediator can stimulate the release of other mediators. These secondary mediators may be
have identical or similar action to the initial mediators but may also have opposing activities.
The more important mediators of acute inflammation are
1. Vasoactive amines
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Histamine and serotonin are stored in cells and are therefore among the first mediators to be released during
inflammation.
a. Histamine
The richest source of this amine is the mast cells that are normally present in the connective tissue adjacent to
blood vessels. It is also found basophils and platelets. Histamine causes dilation of the arterioles and increases
the permeability of venules by binding to receptors on endothelial cells.
b. Serotonin (5-hydroxytryptamine) is present in platelets (and enterochromaffin cells). It has actions similar to
those of histamine.
Release of serotonin and histamine from platelets (platelet release reaction) occurs when platelets aggregate
after contact for e.g. with collagen, thrombin, and antigen-antibody complexes and platelet activating factors
(PAF). They are released by mast cells during IgE-mediated immune reactions.
2. Plasma proteins
These belong to three interrelated systems, the complement, kinin, and clotting systems.
a. The complement System is composed of specific proteins found in greatest concentration in plasma. In the
process of complement activation, a number of complement components are elaborated to mediate a variety of
phenomena in acute inflammation:
i. Vascular phenomena: C3a, C5a stimulate histamine release from mast cells and thereby increase vascular
permeability and cause vasodilation.
ii. Chemoattractants: for e.g. C5a is a powerful chemotactic agent for neutrophils, monocytes, eosinophils, and
basophils.
iii. Opsonins: when fixed to the bacterial cell wall, C3b acts as an opsonin and favor phagocytosis by
neutrophils and macrophages.
b. The kinin System
Initial activation of the kinin system is through the action of XIIa on prekallikrein that lead to the formation of
kallikrein. This occurs following the exposure of blood plasma to vascular basement membrane collagen after
injury to endothelial cells. Kallikrein has a chemotactic activity, and also directly converts C5 to the
chemoattractant C5a. One of the important kinins is the vasoactive bradykinin, which has actions similar to
those of histamine.
c. Clotting System
Activation of the clotting system results in the formation of thrombin. Thrombin generates insoluble fibrin clot.
It also binds to specific receptors expressed on platelets, endothelial and smooth muscle cells, triggering
recruitment of leukocytes. Factor XIIa has two opposing actions; induces clotting and activating the fibrinolytic
system through generation of plasmin, which is important in lysing fibrin clots. Such degradation, leads to the
formation fibrin degradation (split) products (FDP), which may increase vascular permeability. It is evident
from the preceding that coagulation and inflammation are tightly linked. Acute inflammation, by activating or
damaging the endothelium, can trigger coagulation and induce thrombus formation. Conversely, the coagulation
cascade induces inflammation, primarily via the actions of thrombin.
3. PHOSPHOLIPIDS-DERIVED MEDIATORS
A. Arachidonic acid metabolites: prostaglandins, leukotriens, & lipoxins
On cell activation, arachidonic acid (AA), which is a fatty acid, is released from membrane phospholipids
through the action of cellular phospholipase A
2
(activated by C5a). AA metabolites are synthesized by two
major classes of enzymes:
1. Cyclooxygenases (COX) leading to the generation of prostaglandins (PGs) including thromboxane (TxA2)
2. Lipoxygenases that generate leukotrienes and lipoxins
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AA metabolites bind to specific receptors on many cell types and can mediate virtually every step of
inflammation. Suppressors of cyclooxygenase activity (aspirin, nonsteroidal anti-inflammatory drugs, and
COX-2 inhibitors [coxib]) reduce inflammation in vivo.
Several PGs are important in inflammation including PGI2 (prostacyclin), and thromboxane (TxA2). Platelets
contain the enzyme thromboxane synthetase, and hence TxA2 is the major product in these cells. TxA2 is a
potent platelet-aggregating agent and a vasoconstrictor. Vascular endothelium (unlike platelets) lacks
thromboxane synthetase but possesses prostacyclin synthetase, which leads to the formation of prostacyclin.
Prostacyclin, has actions opposing that of TxA2 in that it is a vasodilator, a potent inhibitor of platelet
aggregation. The prostaglandins are also involved in the pathogenesis of pain and fever in inflammation. PGD2
is the major metabolite of the cyclooxygenase (COX) pathway in mast cells; along with PGE2, it causes
vasodilation and increases the permeability of postcapillary venules, thus potentiating edema formation.
In the lipoxygenase pathway, the main products are a family of compounds collectively called leukotrienes.
LTB4 is a potent chemotactic agent and activator of neutrophils.
Lipoxins are a recent addition to the family of bioactive products generated from AA. Leukocytes, particularly
neutrophils, produce lipoxins through their interaction with platelets. The principal actions of lipoxins are to
inhibit neutrophil chemotaxis and adhesion to endothelium.
B. Platelet-activating factor (PAF) is another bioactive phospholipid-derived mediator. A variety of cell types,
including platelets, basophils (and mast cells), neutrophils, monocytes/macrophages, and endothelial cells, can
elaborate PAF. In addition to platelet stimulation, PAF causes vasoconstriction (and bronchospasm), 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, and leukocytes activation. Thus, PAF can elicit
most of the cardinal features of inflammation.
4. CYTOKINES AND CHEMOKINES
Cytokines are proteins produced principally activated lymphocytes and macrophages. In addition to being
involved in cellular immune responses, they also play important roles in both acute and chronic inflammation.
Those relevant to the inflammatory response include Tumor Necrosis Factor (TNF) and Interleukin-1 (IL-1),
which are the major cytokines that mediate inflammation. The secretion of TNF and IL-1 can be stimulated by
endotoxin and other microbial products, immune complexes, and physical injury. Their most important actions
in inflammation are
a. Induce the synthesis of endothelial adhesion molecules and chemical mediators
b. Increase the surface thrombogenicity of the endothelium.
c. Induce the systemic acute-phase responses associated with infection or injury (e.g. fever, loss of appetite,
release of neutrophils into the circulation, the release of corticosteroids).
Chemokines are a family of small proteins that act primarily as chemoattractants for specific types of
leukocytes, for e.g. IL-8 acts primarily on neutrophils. It is secreted by activated macrophages, endothelial cells,
and other cell types and causes activation and chemotaxis of neutrophils, with limited activity on monocytes
and eosinophils. Its most important inducers are microbial products and other cytokines, mainly IL-1 and TNF.
5. NITRIC OXIDE (NO)
NO is a soluble gas that is produced by endothelial cells & macrophages (and some neurons in the brain). Since
the in vivo half-life of NO is only seconds, the gas acts only on cells in close proximity to where it is produced.
NO is a potent vasodilator by virtue of its actions on vascular smooth muscle. In addition, NO reduces platelet
aggregation and adhesion & other inflammatory responses. Thus, production of NO reduces many inflammatory
responses.
Abnormalities in endothelial production of NO occur in atherosclerosis, diabetes, and hypertension.
NO and its derivatives are microbicidal, and thus NO is also a mediator of host defense against infection.
6. LYSOSOMAL CONSTITUENTS OF LEUKOCYTES
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Neutrophils and monocytes/mactophages contain lysosomal granules, which when released may contribute to
the inflammatory response. Neutrophils have two main types of granules
1. The smaller specific (or secondary) granules that contain lysozyme, collagenase, gelatinase, lactoferrin,
plasminogen activator, etc.
2. The large azurophil (or primary) granules that contain myeloperoxidase, bactericidal factors (lysozyme,
defensins), acid hydrolases, and neutral proteases (e.g. collagenases, proteinase 3).
Both types of granules can empty into phagocytic vacuoles that form around engulfed material, or the granule
contents can be released into the extracellular space. Different granule enzymes serve different functions. Acid
proteases degrade bacteria and debris within the phagolysosomes, in which a low (acid) pH is readily reached.
Neutral proteases are capable of degrading various extracellular components. These enzymes can attack
collagen, basement membrane, fibrin, elastin, and cartilage, resulting in the tissue destruction that accompanies
inflammatory processes. Neutrophil elastase has been shown to degrade virulence factors of bacteria and thus
combat bacterial infections. Monocytes and macrophages also contain acid hydrolases, collagenase, elastase,
phospholipase, and plasminogen activator. These may be particularly active in chronic inflammatory reactions.
Because of the destructive effects of lysosomal enzymes, the initial leukocytic infiltration, if unchecked, can
potentiate further increases in vascular permeability and tissue damage. These harmful proteases, however, are
held in check by a system of antiproteases in the serum and tissue fluids. Foremost among these is α
1
-
antitrypsin, which is the major inhibitor of neutrophil elastase. A deficiency of these inhibitors may lead to
sustained action of leukocyte proteases (progressive tissue damage), as is the case in patients with α
1
-antitrypsin
deficiency.
7. OXYGEN-DERIVED FREE RADICALS
Oxygen-derived free radicals may be released extracellularly from leukocytes after exposure to microbes,
chemokines, and immune complexes. Superoxide anion (O
-
2
) hydrogen peroxide (H
2
O
2
), and hydroxyl radical
(OH) are the major species produced within the cell. Extracellular release of low levels of these potent
mediators can amplify the inflammatory response. The physiologic function of these reactive oxygen
intermediates is to destroy phagocytosed microbes. At higher levels, release of these potent mediators can
damage the tissues. Serum, tissue fluids, and host cells possess antioxidant mechanisms that protect against
these potentially harmful oxygen-derived radicals. The influence of oxygen-derived free radicals in any given
inflammatory reaction depends on the balance between the production and the inactivation of these metabolites
by cells and tissues.
8. NEUROPEPTIDES
Neuropeptides, similar to the vasoactive amines and the AA metabolites, play a role in the initiation and
propagation of an inflammatory response. They include substance P, which has many biologic functions,
including the transmission of pain signals, regulation of blood pressure, and increasing vascular permeability.
9. OTHER MEDIATORS
The mediators described above account for inflammatory reactions to microbes, toxins, and many types of
injury, but may not explain why inflammation develops in some specific situations. Recent studies are
providing clues about the mechanisms of inflammation in two frequently encountered pathologic conditions.
a. Response to hypoxia
It is known that hypoxia causes cell injury and necrosis. However, it is also an inducer of the inflammatory
response. The latter is mediated by a protein called hypoxia-induced factor 1α, which is produced by cells
deprived of oxygen and activates many genes involved in inflammation; one of these leads to the production of
vascular endothelium growth factor (VEGF), which increases vascular permeability.
b. Response to necrotic cells
It is well known that necrotic cells elicit inflammatory reactions that serve to eliminate these cells. One
participant may be uric acid, which is a product of necrotic cell’s DNA breakdown. Uric acid crystallizes when
present at sufficiently high concentrations in extracellular tissues. Uric acid crystals stimulate inflammation and
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subsequent immune response. This inflammatory action of uric acid is the basis of the disease gout, in which
excessive amounts of uric acid are produced and crystals deposit in joints and other tissues.
MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION
Many variables may modify the basic inflammatory response; these include
1. The nature and intensity of the injury
2. The site and tissues affected
3. The responsiveness of the host
Several types of inflammation are recognized, which vary in their morphology and clinical correlates.
Serous inflammation is characterized by the outpouring of a thin fluid that is derived from either the plasma or
the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities. In these serous cavities
the accumulated fluid is called effusion. (Fig. 3-5) 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 more severe injuries and the resulting greater vascular permeability, larger molecules such as fibrinogen
pass the vascular barrier, and fibrin is formed and deposited in the extracellular space. A fibrinous exudate
develops in such cases. The latter also occurs when there is a stimulus for coagulation in the interstitium (e.g.,
cancer cells). A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the
meninges, pericardium, and pleura. (Fig. 3-6) Microscopically, fibrin appears as an eosinophilic meshwork of
threads or amorphous coagulated mass. Fibrinous exudates may be removed by fibrinolysis and clearing of
other debris by macrophages. However, when the fibrin is not removed, it may stimulate the ingrowth of
fibroblasts and blood vessels and thus lead to scarring. Conversion of the fibrinous exudate to scar tissue is
called organization. When this occurs within the pericardial sac it leads either to opaque fibrous thickening of
the pericardium or, more often, to the development of fibrous strands that reduce and may even obliterate the
pericardial space.
Suppurative (purulent) inflammation
This is characterized by the production of large amounts of pus or purulent exudate consisting of neutrophils,
necrotic cells, and edema fluid. Certain bacteria (e.g., staph. aureus, St. pyogenes, Pneumococci, gonococci,
meningococci and E. coli) produce this localized suppuration and are therefore called pyogenic (pus-producing)
bacteria. A common example of an acute suppurative inflammation is acute (suppurative) appendicitis. (Fig.
3-7)
An abscess is a localized collection of purulent inflammatory fluid (pus) caused by suppuration buried in a
tissue, an organ, or a confined space. Pus is a thick creamy yellow or blood-stained fluid. Abscesses are
produced by deep seeding of pyogenic bacteria into a tissue. They have a central region that appears as a mass
of necrotic leukocytes and tissue cells. There is usually a zone of preserved neutrophils around this necrotic
focus, and outside this region vascular dilation and fibroblastic proliferation occur, indicating the beginning of
repair. In time, the abscess may become walled off and ultimately replaced by connective tissue. A common
example of an abscess is the skin furuncle. (Fig. 3-8)
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 inflammatory necrotic tissue. Ulceration occurs only when tissue necrosis and resultant
inflammation exist on or near a surface. It is most commonly encountered in:
1. Inflammatory necrosis of mucosa-lined cavities e.g. mouth, larynx, stomach, intestines, or genitourinary tract.
(Fig. 3-9)
2. Subcutaneous inflammation of the lower extremities in older persons who have circulatory disturbances that
predispose to extensive necrosis.
Ulcerations are best exemplified by peptic ulcer of the stomach or duodenum, in which acute and chronic
inflammation coexist.
Pseudomembranous inflammation of mucous membranes
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Severe injury may be associated with extensive epithelial necrosis with sloughing. This creates large shallow
ulcers. Fibrin, dead epithelium, neutrophils, red cells and bacteria mix together to produce a white or cream-
colored false (pseudo-) membrane covering the affected mucosa.
Diphtheria and psudomembranous colitis are typical examples. (Fig. 3-10)
EFFECTS OF ACUTE INFLAMMATION
Beneficial Effects
1. Dilution of Toxins by the edema fluid
2. Production of protective Antibodies & promotion of immunity
3. Fibrin meshwork formation that forms a scaffold for inflammatory cell migration &
also limits the
spread of infections
4. Cell Nutrition
Harmful Effects
1. Swelling & edema that can be detrimental for e.g. acute epiglottitis that may be life
threatening
(Fig. 3-11)
2. Rise in tissue pressure that contributes to tissue necrosis
3. Digestion of adjacent viable tissue
4. Sever damaging allergic reaction
5. Generalized increase in vascular permeability can cause shock as seen in
anaphylactic
reactions.
OUTCOMES OF ACUTE INFLAMMATION
In general, acute inflammation may have one of three outcomes
1. Complete resolution
The battle between the injurious agent and the host may end with restoration of the site of acute inflammation to
normal. This is called resolution and is the usual outcome when
a. the injury is limited or short-lived
b. there has been little tissue destruction
c. the damaged parenchymal cells can regenerate
2. Healing by fibrosis
This occurs
a. after extensive tissue destruction
b. when the inflammatory injury involves tissues that are incapable of regeneration
c. when there is abundant fibrin exudation.
When the fibrinous exudate in tissue or serous cavities (pleural, peritoneal, synovial) cannot be adequately
cleared, connective tissue grows into the area of exudate, converting it into a mass of fibrous tissue—a process
also called organization.
3. Progression to chronic inflammation
Acute to chronic transition occurs when the acute inflammatory response persists, owing either to the
perseverance of the injurious agent or to some interference with the normal process of healing. For example,
failure of acute bacterial pneumonia 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.
CHRONIC INFLAMMATION
Although it may follow acute inflammation, it frequently begins from the outset as a chronic (chronic
inflammation ab initio), insidious, and low-grade, smoldering response. Chronic inflammation is the cause of
tissue damage in some of the most common and disabling human diseases, such as rheumatoid arthritis,
atherosclerosis, tuberculosis, and chronic lung diseases.
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Chronic Inflammation may complicate acute inflammation. The latter is almost always a suppurative type of
inflammation that presents as a purulent discharge (pus) as seen in abscess. The cause is either a delay in the
evacuation of an abscess, or presence of foreign-body within inflamed area (dirt, wood, metal or a sequestrated
bone)
Causes of chronic inflammation ab initio include
1. Persistent infections by certain microorganisms such as tubercle bacilli, Treponema pallidum, certain viruses,
fungi, and parasites. These organisms are of low toxicity and evoke delayed type hypersensitivity reaction.
2. Prolonged exposure to toxic agents either exogenous as inhaled silica particles, or endogenous such as toxic
plasma lipids that are thought to be responsible for atherosclerosis. The latter is thought to be a chronic
inflammatory process of the arterial wall.
3. Autoimmunity
Under certain conditions, immune reactions develop against the individual's own tissues, leading to autoimmune
diseases. In these diseases, autoantigens activate a self-perpetuating immune reaction that results in chronic
inflammation with associated tissue damage. Examples of this type include several common chronic
inflammatory diseases, such as rheumatoid arthritis and lupus erythematosus.
Morphologic features of chronic inflammation
In contrast to acute inflammation, which is manifested by vascular changes, edema, and predominantly
neutrophilic infiltration, chronic inflammation is characterized by:
1. Infiltration with mononuclear cells including macrophages, lymphocytes, and plasma cells.
2. Tissue destruction, induced by the persistent offending agent or by the inflammatory cells.
3. Attempts at healing by fibrosis of the damaged tissue, achieved by proliferation of small blood vessels
(angiogenesis) & fibroblasts. (Fig. 3-12)
Mononuclear cell infiltration
The macrophage is the dominant cells in chronic inflammation. The mononuclear phagocyte system
(reticuloendothelial system) consists of closely related cells of bone marrow origin, including blood monocytes
and tissue macrophages. The latter are diffusely scattered in connective tissues or located in organs such as the
liver (Kupffer cells), spleen and lymph nodes (sinus histiocytes), and lungs (alveolar macrophages). 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 the
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 cytokines (e.g., IFN-γ) secreted
by sensitized T lymphocytes, NK cells, bacterial endotoxins, and other chemical mediators. Activation results in
increased cell size, and greater ability to phagocytose and kill ingested microbes. Activated macrophages
secrete a wide variety of biologically active products that result in the tissue injury and fibrosis. In short-lived
acute inflammation, if the irritant is eliminated, macrophages eventually disappear (dying off or travel through
lymphatics to lymph nodes). In chronic inflammation, macrophage accumulation persists, and this is mediated
by the following:
1. Recruitment from circulating monocytes; a process fundamentally similar to that of neutrophils.
2. Local proliferation of macrophages after their emigration from the bloodstream. This is now known to occur
prominently in some chronic inflammatory lesions, such as atheromatous plaques.
3. Immobilization of macrophages within the site of inflammation. Certain cytokines and oxidized lipids can
cause such immobilization (migration inhibiting factors).
The products of activated macrophages serve to eliminate injurious agents such as microbes and to initiate the
process of repair, but are also responsible for much of the tissue injury in chronic inflammation; these products
include
1. Toxic substances to microbes and host cells (e.g., toxic O2 species, NO, and proteases)
2. Chemoattractants to other inflammatory cells
3. Growth factors the cause of fibroblast proliferation, collagen deposition, and angiogenesis.
Other cells in chronic inflammation
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Other cell types present in chronic inflammation include lymphocytes, plasma cells, eosinophils, and mast cells:
Lymphocytes are mobilized in immune and nonimmune inflammation. Antigen-stimulated T and B-cells use
various adhesion molecules (predominantly the integrins) and chemokines to migrate into inflammatory sites.
Lymphocytes and macrophages interact in a bidirectional way and these reactions play an important role in
chronic inflammation. Macrophages display antigens to T cells that stimulate them. Activated T lymphocytes
produce cytokines, and one of these, IFN-γ, which is a major activator of macrophages.
Plasma cells develop from activated B lymphocytes and produce antibody directed against persistent antigen in
the inflammatory site.
Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections. The recruitment of
eosinophils involves extravasation from the blood and their migration into tissue by processes similar to those
for other leukocytes. One of the chemokines that is especially important for eosinophil recruitment is eotaxin.
Eosinophils have granules that contain major basic protein that is toxic to parasites.
Mast cells are widely distributed in connective tissues and participate in both acute and persistent inflammatory
reactions. Mast cells express on their surface the receptor that binds the Fc portion of IgE antibody. In acute
reactions, IgE antibodies bound to the cells' Fc receptors specifically recognize antigen, and the cells
degranulate and release mediators, such as histamine and products of AA oxidation. Mast cells are also present
in chronic inflammatory reactions, and may produce cytokines that contribute to fibrosis.
Neutrophils although characteristic of acute inflammation, many forms of chronic inflammation continue to
show large numbers of neutrophils, induced either by persistent microbes or by mediators produced by
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.
Mediators of chronic inflammation (Fig. 3-13)
Examples of chronic inflammation
Chronic Cholecystitis may be the sequel to repeated bouts of acute cholecystitis, but in most instances it
develops de novo. Like acute cholecystitis it is almost always associated with gallstones but these do not
seem to have a direct role in the initiation of inflammation. Rather, supersaturation of bile predisposes to both
chronic inflammation and, in most instances, stone formation. Microorganisms, usually E. coli and enterococci,
can be cultured from the bile in only about one-third of cases. The gallbladder may be contracted, of normal
size, or enlarged. The submucosa and subserosa are often thickened from fibrosis. In the absence of
superimposed acute cholecystitis, mural lymphocytes are the only feature of inflammation. (Fig. 3-14)
GRANULOMATOUS INFLAMMATION
This is a distinctive pattern of chronic inflammatory reaction characterized by focal accumulations of activated
macrophages, which often develop an epithelioid (epithelial-like) appearance.
Causes
Granulomatous inflammation is encountered in a number of immunologically mediated infectious and some
noninfectious conditions, these include
1. Tuberculosis
2. Sarcoidosis
3. Cat-scratch disease
4. Lymphogranuloma inguinale
5. Leprosy
Recognition of granulomas in a biopsy specimen is important because it shortens the list of the differential
diagnosis. A granuloma is a focus of chronic inflammation consisting of a microscopic aggregation of
macrophages that are transformed into epithelioid cells surrounded by a collar of mononuclear leukocytes,
principally lymphocytes and occasionally plasma cells. The epithelioid cells have a pale pink granular
cytoplasm with indistinct cell borders and a vesicular nucleus that is oval or elongate. Older granulomas
6. Brucellosis
7. Syphilis,
8. Some fungal infections
9. Berylliosis
10. Reactions of irritant lipids
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develop an enclosing rim of fibroblasts and connective tissue. Frequently, epithelioid cells fuse to form giant
cells in the periphery or sometimes in the center of granulomas. These giant cells may attain diameters of 40 to
50 µm. (Fig. 3-15) They have a large mass of cytoplasm containing 20 or more 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.
1. Foreign body granulomas, which are provoked by foreign bodies. Typically, foreign body granulomas form
when material such as talc (associated with intravenous drug abuse), sutures, or other fibers are large enough to
preclude phagocytosis by a single macrophage and do not incite any specific inflammatory or immune response.
Epithelioid cells and giant cells form and are apposed to the surface of the foreign body and/or actually include
it. The foreign material can usually be identified in the center of the granuloma, particularly if viewed with
polarized light, in which it appears refractile. (Fig. 3-16)
2. Immune granulomas; these are caused by insoluble, poorly degradable or particulate particles, typically
microbes that are capable of inducing a cell-mediated immune response. In these responses, macrophages
engulf the inciting agent, process it, and present some of it to appropriate T lymphocytes, causing them to
become activated. The responding T cells produce cytokines, such as IL-2, which activates other T cells,
perpetuating the response, and IFN-γ, which is important in activating macrophages and transforming them into
epithelioid cells and multinucleate giant cells.
The typical example of an immune granuloma is that caused M. tuberculosis. In tuberculosis, the granulomatous
reaction is referred to as a tubercle and is classically characterized by the presence of central caseous necrosis,
whereas caseation is rare in other granulomatous diseases. (Fig. 3-17) It is always necessary to identify the
specific etiologic agent by special stains for organisms (e.g., acid-fast stains for tubercle bacilli), by culture
methods (e.g., in tuberculosis and fungal diseases), by molecular techniques (e.g., the polymerase chain reaction
in tuberculosis), and by serologic studies (e.g., in syphilis). In sarcoidosis, the etiologic agent is unknown and
the diagnosis is that of exclusion. (Fig. 3-18)
LYMPHATICS IN INFLAMMATION
Lymph nodes filters the extravascular fluids brought to them by lymphatic vessels. They represent a secondary
line of defense that operates whenever a local inflammatory reaction fails to contain and neutralize an external
agent, such as a microbe.
Lymphatics are delicate channels that are difficult to visualize in ordinary tissue sections because they readily
collapse. In inflammation lymph flow is increased and helps drain the edema fluid from the extravascular space.
Not only fluid, but also leukocytes and cell debris may find their way into lymph. The drainage may transport
the offending agent (chemical or microbial). The lymphatics may become secondarily inflamed (lymphangitis),
as may the draining lymph nodes (lymphadenitis). Therefore, it is not uncommon in infections of the hand, for
example, to observe red streaks along the entire arm up to the axilla following the course of the lymphatics
(lymphangitis), accompanied by painful enlargement of the axillary lymph nodes (lymphadenitis). The nodal
enlargement is usually caused by hyperplasia of the lymphoid follicles as well as by hyperplasia of the
phagocytic cells lining the sinuses of the lymph nodes (reactive or inflammatory lymphadenitis). In severe
infections, the lymph nodes may be overwhelmed and fail to halt the spread of infection. The organisms gain
access to the vascular circulation, thus inducing a bacteremia. The phagocytic cells of the liver, spleen, and
bone marrow constitute the next line of defense, but in massive infections, bacteria seed distant tissues of the
body. The heart valves, meninges, kidneys, and joints are favored sites of implantation for blood-borne
organisms, and when this happens; endocarditis, meningitis, renal abscesses, and septic arthritis may develop.
SYSTEMIC EFFECTS OF INFLAMMATION
The systemic changes associated with inflammation, especially infections, are collectively called the acute
phase response (Systemic inflammatory response syndrome [SIRS]). These changes are reactions to cytokines
produced in response to bacterial infections and other inflammatory stimuli. The acute phase response
consists of several clinical and pathologic changes:
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1. Fever is a prominent manifestation; it is produced in response to pyrogens that act by stimulating PG
synthesis in the vascular and perivascular cells of the hypothalamus.
2. Acute-phase proteins are plasma proteins, mostly synthesized in the liver, and whose plasma concentrations
may increase several hundred times in inflammation. The best-known of these are
a. C-reactive protein (CRP)
b. Fibrinogen
c. Serum amyloid A protein (SAA).
CRP and SAA, bind to microbial cell walls acting as opsonins and fixing complement. The rise in fibrinogen
causes erythrocytes to form stacks (rouleaux) that sediment more rapidly than individual erythrocytes. This is
the basis for the elevation of the ESR. Prolonged production of SAA causes secondary amyloidosis in
destructive chronic inflammations (e.g. rheumatoid arthritis). Elevated serum levels of CRP are now used as a
marker for increased risk of myocardial infarction in patients with atherosclerotic coronary artery disease. The
inflammation involving atherosclerotic plaques in the coronary arteries may predispose to thrombosis and
subsequent infarction, and CRP is produced during inflammation. On this basis, anti-inflammatory agents are
being tested in patients to reduce the risk of myocardial infarction.
3. Leukocytosis is a common feature of the acute phase response, especially those induced by bacterial
infection. The leukocyte count usually rises to 15,000 or 20,000 cells/µl, but sometimes it may reach very high
levels of 40,000 to 100,000 cells/µl. These extreme elevations are referred to as leukemoid reactions because
they are similar to the white cell counts obtained in leukemia. The leukocytosis occurs initially because of
accelerated release of cells from the bone marrow reserve pool (induced by cytokines, including IL-1 and TNF)
and is therefore associated with a rise in the number of more immature neutrophils in the blood (shift to the
left). Prolonged infection also induces proliferation of precursors in the bone marrow, caused by increased
production of colony stimulating factors (CSFs). Neutrophilia refers to an increase in the blood neutrophil
count. Most bacterial infections induce neutrophilia. Viral infections such as infectious mononucleosis, mumps,
and German measles produce a leukocytosis due to absolute lymphocytosis. In bronchial asthma, hay fever, and
parasitic infestations, there is an absolute increase in the number of eosinophils, creating an eosinophilia.
Certain infections (typhoid fever and infections caused by viruses, rickettsiae, and certain protozoa) are
associated with a decreased number of circulating white cells (leukopenia). Leukopenia is also encountered in
infections that overwhelm patients debilitated by disseminated cancer or uncontrolled tuberculosis.
4. Other manifestations of the acute phase response include increased pulse and blood pressure; decreased
sweating; rigors, and anorexia.
5. Disseminated intravascular coagulation (DIC) & septic shock: in severe bacterial infections (sepsis), the large
amounts of organisms and lipopolysaccharides (LPS) in the blood stimulate the production of enormous
quantities of TNF and IL-1. High levels of TNF cause DIC. LPS and TNF induce tissue factor (TF) expression
on endothelial cells, which initiates coagulation; the same agents inhibit natural anticoagulation mechanisms.
Cytokines cause liver injury and impaired liver function, resulting in a failure to maintain normal blood glucose
levels due to a lack of gluconeogenesis from stored glycogen. Overproduction of NO by cytokine-activated
cardiac myocytes and vascular smooth muscle cells leads to heart failure and loss of perfusion pressure,
respectively, resulting in cardiogenic shock. The clinical triad of DIC, hypoglycemia, and cardiovascular failure
is described as septic shock. Multiple organs show inflammation and intravascular thrombosis, which can
produce organ failure. Lung damage (adult respiratory distress syndrome [ARDS]) results when neutrophil-
mediated endothelial injury allows fluid to escape from the blood into the airspaces. The kidney and the bowel
are also injured, largely due to reduced perfusion. Septic shock is often fatal.
CONSEQUENCES OF DEFECTIVE OR EXCESSIVE INFLAMMATION
Defective inflammation typically results in
1. Increased susceptibility to infections
2. Delayed healing or repair of wounds
3. Tissue damage
15
Delayed repair is due to the fact that the inflammatory response provides the necessary stimulus to get the repair
process started.
Excessive inflammation is the basis of many categories of human disease that include allergies and
autoimmune diseases.
Recent studies, however, are pointing to an important role of inflammation in a wide variety of human diseases
that are not primarily disorders of the immune system. These include
1. Cancer
2. Atherosclerosis
3. Ischemic heart disease
4. Some neurodegenerative diseases such as Alzheimer disease.
In addition, prolonged inflammation and the fibrosis that accompanies it are responsible for much of the
pathology in many chronic infectious, metabolic and other diseases. Since these disorders are some of the major
curses of mankind, it is not surprising that the normally protective inflammatory response is being called the
"silent killer".