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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).
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
. 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 and increased blood flow
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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.
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
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(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
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 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.
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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.. 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.
CHEMICAL MEDIATORS OF INFLAMMATION
Chemical mediators are substances that are responsible for many of the inflammatory
events. According to their origin, they are either
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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
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
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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.
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 A2 (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
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
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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
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).
7. OXYGEN-DERIVED FREE RADICALS
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Oxygen-derived free radicals may be released extracellularly from leukocytes after
exposure to microbes, chemokines, and immune complexes. Superoxide anion (O- 2)
hydrogen peroxide (H2O2), 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
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
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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)
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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
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
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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.
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
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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).
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
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.
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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 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.
6. Brucellosis
7. Syphilis,
8. Some fungal infections
9. Berylliosis
10. Reactions of irritant lipids
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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)
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:
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).
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
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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).
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.
