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Overview of Inflammation
 Inflammation – host response that allows body to get rid of damaged or necrotic tissues and foreign invaders
o Fundamentally protective response designed to rid body of both initial cause of cell injury (e.g.,
microbes, toxins) and consequences of such injury (e.g., necrotic cells and tissues)
 Inflammation – complex reaction in tissues that consists mainly of responses of blood vessels and leukocytes
o Body’s principal defenders against foreign invaders are plasma proteins and circulating leukocytes, as
well as tissue phagocytes derived from circulating cells
o Because invaders typically present in tissues outside circulation, circulating cells and proteins have to be
rapidly recruited to extravascular sites; inflammatory response coordinates reactions of vessels,
leukocytes, and plasma proteins
 Vascular and cellular reactions of inflammation triggered by soluble factors produced by various cells or derived
from plasma proteins and are generated or activated in response to inflammatory stimulus
o Microbes, necrotic cells, and hypoxia can trigger elaboration of inflammatory mediators and elicit
inflammation; above mediators initiate and amplify inflammatory response and determine its pattern,
severity, and clinical and pathologic manifestations
 Main characteristics of acute inflammation are exudation of fluid and plasma proteins (edema) and emigration
of leukocytes, predominantly neutrophils
o When acute inflammation successful in eliminating offenders, reaction subsides
 Chronic inflammation – occurs when acute inflammation fails to fix problem; associated with presence of
lymphocytes and macrophages, proliferation of blood vessels, fibrosis, and tissues destruction
 Inflammation terminated when offending agent eliminated; reaction resolves rapidly because mediators broken
down and dissipated and leukocytes have short life spans in tissues
o Anti-inflammatory mechanisms activated that serve to control response and prevent it from causing
excessive damage to host
 Inflammatory response closely intertwined with process of repair (sets into motion series of events that try to
heal damaged tissue)
o Repair reaches completion usually after injurious influence has been neutralized
o In process of repair, injured tissue replaced through regeneration of native parenchymal cells by filling
defect with fibrous tissue (scarring) or most commonly by combining the two
 Chronic inflammation may play role in atherosclerosis, type 2 DM, degenerative disorders like Alzheimer, and
cancer
Historical Highlights
 Celsus – first listed the four cardinal signs of inflammation on Egyptian papyrus around 3000 BC (redness,
swelling, heat, and pain)
 Fifth clinical sign (loss of function) added by Rudolf Virchow in 19th century
 In 1793, Scottish surgeon John Hunter noted inflammation is not a disease but a nonspecific response that has
salutary effect on host
 In 1880s, Russian biologist Elie Metchnikoff discovered process of phagocytosis and concluded that purpose of
inflammation was to bring phagocytic cells to injured area to engulf invading bacteria
 Sir Thomas Lewis established concept that chemical substances, such as histamine, mediate vascular changes of
inflammation (concept underlies important discoveries of chemical mediators of inflammation and use of antiinflammatory drugs in clinical medicine
Acute Inflammation
 3 major components: alterations in vascular caliber that lead to increase in blood flow, structural changes in
microvasculature that permit plasma proteins and leukocytes to leave circulation, and emigration of leukocytes
from microcirculation, their accumulation in focus of injury, and their activation to eliminate offending agent
 Acute inflammatory reactions may be triggered by
o Infections (bacterial, viral, fungal, parasitic) and microbial toxins
 Family of Toll-like receptors (TLRs) and several cytoplasmic receptors detect bacteria, viruses,
and fungi
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Engagement of receptors triggers signaling pathways that stimulate production of various
mediators
o Tissue necrosis – several molecules released form necrotic cells elicit inflammation (uric acid, ATP, DNAbinding protein called HMGB-1, and DNA when released into cytoplasm and not sequestered in nuclei
 Hypoxia is inducer of inflammatory response; mediated largely by HIF-1α, which is produced by
cells deprived of oxygen and activates transcription of many genes involved in inflammation,
including VEGF, which increases vascular permeability
o Foreign bodies (splinters, dirt, sutures) typically elicit inflammation because they cause traumatic tissue
injury or carry microbes
o Immune reactions (hypersensitivity reactions) in which normally protective immune system damages
individual’s own tissues
 Can be either autoimmune or allergenic
 Inflammation is major cause of tissue injury in these cases
 Inflammation induced by cytokines produced by T lymphocytes and other cells of immune
system
 Often called immune-mediated inflammation
In inflammation, blood vessels undergo series of changes designed to maximize movement of plasma proteins
and circulating cells out of circulation and into site of infection or injury
Exudation – escape of fluid, proteins, and blood cells from vascular system into interstitial tissue or body cavities
Exudate – extra-vascular fluid with high protein concentration that contains cellular debris and has high specific
gravity; presence of exudate implies increase in normal permeability of small blood vessels in area of injury (and
therefore inflammatory reaction)
Transudate – fluid with low protein content, little or no cellular material, and low specific gravity; essentially
ultra-filtrate of blood plasma that results from osmotic or hydrostatic imbalance across vessel wall without
increase in vascular permeability
Edema – can be either exudate or transudate
Pus – purulent exudate that is rich in leukocytes (mostly neutrophils), debris of dead cells, and in many cases
microbes
Changes in vascular flow and caliber begin early after injury and consist of
o Vasodilation – one of earliest manifestations of acute inflammation; sometimes follows transient
constriction of arterioles, lasting a few seconds
 Vasodilation first involves arterioles and leads to opening of new capillary beds in area, resulting
in increased blood flow, which is cause of erythema at site of inflammation
 Induced by action of mostly histamine and NO on vascular smooth muscle
o Increased permeability of microvasculature with outpouring of protein-rich fluid into extravascular
tissues
o Loss of fluid and increased vessel diameter lead to slower blood flow, concentration of RBCs in small
vessels, and increased viscosity of blood; results in dilation of small vessels packed with slowly moving
RBCs (stasis) seen as vascular congestion (producing localized redness)
o As stasis develops, blood leukocytes (principally neutrophils) accumulate along vascular endothelium
 Endothelial cells activated by mediators produced at sites of infection and tissue damage and
express increased levels of adhesion molecules
 Leukocytes adhere to endothelium and migrate through vascular wall into interstitial tissue
Mechanisms responsible for increased vascular permeability – can work together in varying degrees to respond
to most stimuli; at different stages of burn, leakage results from chemically mediated endothelial contraction
and direct and leukocyte-dependent endothelial injury
o Contraction of epithelial cells resulting in increased inter-endothelial spaces – most common mechanism
of vascular leakage; elicited by histamine, bradykinin, leukotrienes, neuropeptide substance P, and many
other chemical mediators
 Immediate transient response because it occurs rapidly after exposure to mediator and is
usually short-lived
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In some forms of mild injury, vascular leakage begins after delay of 2-12 hours and lasts for
several hours to days – delayed prolonged leakage that may be caused by contraction of
endothelial cells or mild endothelial damage (e.g., late appearing sunburn)
o Endothelial injury, resulting in endothelial cell necrosis and detachment – direct damage to endothelium
 Neutrophils that adhere to endothelium during inflammation may also injure endothelial cells
and amplify reaction
 In most instances, leakage starts immediately after injury and is sustained for several hours until
damaged vessels thrombosed or repaired
o Transcytosis – increased transport of fluids and proteins through endothelial cells
 May involve channels consisting of interconnected, uncoated vesicles and vacuoles
(vesiculovacuolar organelle), many of which located close to intracellular junctions
 Factors such as VEGF promote vascular leakage by increasing number and size of channels
In inflammation, lymph flow increased and helps drain edema fluid that accumulates due to increased vascular
permeability; leukocytes and cell debris, as well as microbes, go into lymph
o Lymphatic vessels proliferate during inflammatory reactions to handle increased load
o Lymphatics may become secondarily inflamed (lymphangitis) or draining lymph nodes may become
inflamed (lymphadenitis)
o Inflamed lymph nodes often enlarged because of hyperplasia of lymphoid follicles and increased
numbers of lymphocytes and macrophages (reactive or inflammatory lymphadenitis)
o Presence of red streaks near skin wound is telltale sign of infection in wound; streaking follows course of
lymphatic channels and is diagnostic of lymphangitis; may be accompanied by painful enlargement of
draining lymph nodes, indicating lymphadenitis
Neutrophils and macrophages ingest and kill bacteria and other microbes and eliminate necrotic tissue and
foreign substances
o Leukocytes produce growth factors that aid in repair
o When strongly activated, leukocytes may induce tissue damage and prolong inflammation because
leukocyte products destroy microbes and necrotic tissue but can also injure normal host cells
Extravasation of leukocytes divided into
o In lumen – margination, rolling, and adhesion to endothelium; vascular endothelium doesn’t usually
bind circulating cells or impede their passage, but in inflammation, endothelium activated and can bind
leukocytes as prelude to their exit from blood vessels
o Migration across endothelium and vessel wall
o Migration in tissues toward chemoctactic stimulus
In normally flowing blood in venules, RBCs confined to central axial column, displacing leukocytes toward wall of
vessel; because blood flow slows in early inflammation (stasis), hemodynamic changes change (wall shear stress
decreases), and more WBCs assume peripheral position along endothelial surface (margination)
o Individual and then rows of leukocytes adhere transiently to endothelium, detach and bind again, rolling
on vessel wall; cells finally come to rest at some point where they adhere firmly (pebbles in a stream)
o Adhesion of leukocytes to endothelial cells mediated by complementary adhesion molecules on cells
whose expression is enhanced by cytokines
 Cytokines secreted by cells in tissues in response to microbes and other injurious agents,
ensuring leukocytes recruited to tissues where stimuli present
o Initial rolling interactions mediated by selectins
 L-selectin expressed on leukocytes
 E-selectin expressed on endothelium
 P-selectin expressed on platelets and endothelium
o Ligands for selectins sialylated oligosaccharides bound to mucin-like glycoprotein backbones
o Expression of selectins and ligands reulated by cytokines produced in response to infection and injury
o Tissue macrophages, mast cells, and endothelial cells that encounter microbes and dead tissues respond
by secreting several cytokines, including TNF, IL-1, and chemokines
 TNF and IL-1 act on endothelial cells of post-capillary venules adjacent to infection and induce
coordinate expression of numerous adhesion molecules
o In 1-2 hours, endothelial cells begin to express E-selectin and ligands for L-selectin
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Histamine, thrombin, and PAF stimulate redistribution of P-selectin from normal intracellular stores in
endothelial cell granules (Weibel-Palade bodies) to cell surface
o Leukocytes express L-selectin at tips of microvilli and ligands for E and P-selectins
 Low-affinity interactions with fast off-rate, easily disrupted by flowing blood
 Bound leukocytes bind, detach, and bind again (rolling); weak rolling interactions slow down
leukocytes and give them opportunity to bind more firmly to endothelium
o Firm adhesion mediated by family of heterodimeric leukocyte surface proteins (integrins)
 TNF and IL-1 induce endothelial expression of ligands for integrins, mainly VCAM-1 (ligand for
VLA-4 integrin) and ICAM-1 (ligand for LFA-1 and Mac-1 integrins)
o Leukocytes normally express integrins in low-affinity state
o Chemokines produced at site of injury enter blood vessel, bind to endothelial cell proteoglycans, and are
displayed at high concentrations on endothelial surface
 Chemokines bind to and activate rolling leukocytes
 Activation causes conversion of VLA-4 and LFA-1 integrins on leukocytes to high-affinity state
 Combination of cytokine-induced expression of integrin ligands on endothelium and activation
of integrins on leukocytes results in firm integrin-mediated binding of leukocytes to endothelium
at site of inflammation
 Leukocytes stop rolling, cytoskeleton is reorganized, and they spread out on endothelial surface
Migration of leukocytes through endothelium – diapedesis; occurs mainly in post-capillary venules
o Chemokines act on adherent leukocytes and stimulate cells to migrate through inter-endothelial spaces
toward chemical concentration gradient of chemokines
o Adhesion molecules in intercellular junctions between endothelial cells include PECAM-1 (member of Ig
superfamily), CD31, and several junctional adhesion molecules
o After traversing endothelium, leukocytes pierce basement membrane by secreting collagenases and
enter extravascular tissue
o Cells migrate toward chemotactic gradient created by chemokines and accumulate in extravascular site
o In CT, leukocytes able to adhere to ECM by virtue of integrins and CD44 binding to matrix proteins, so
leukocytes retained at site where they are needed
o Genetic deficiencies in leukocyte adhesion molecules results in recurrent bacterial infections as
consequence of impaired leukocyte adhesion and defective inflammation
 Leukocyte adhesion deficiency type 1 – defect in biosynthesis of β2 chain shared by LFA-1 and
Mac-1 integrins
 Leukocyte adhesion deficiency type 2 – caused by absence of sialyl-Lewis X (fucose-containing
ligand for E and P-selectins) as result of defect in fucosyl transferase (enzyme that attaches
fucose moieties to protein backbones)
After exiting circulation, leukocytes emigrate toward site of injury by chemotaxis; both exogenous and
endogenous substances can act as chemoattractants
o Most common exogenous agents are bacterial products, including peptides that possess Nformylmethionine terminal amino acid, and some lipids
o Endogenous chemoattractants include cytokines (particularly those of chemokine family like IL-8),
components of complement system (particularly C5a), and arachidonic acid (AA) metabolites, mainly
leukotriene B4 (LTB4)
o Chemotactic agents bind to specific 7-transmembrane G protein-coupled receptors on surface of
leukocytes; signals initiated from receptors result in activation of second messengers that increase
cytosolic calcium and activate small GTPs of Rac/Rho/cdc42 family as well as numerous kinases
o Signals induce polymerization of actin, resulting in increased amounts of polymerized actin at leading
edge of cell and localization of myosin filaments at back
o Leukocyte moves by extending filopodia that pull back of cell in direction of extension
In most forms of acute inflammation, neutrophils predominate in inflammatory infiltrate during first 6-24 hours
and are replaced by monocytes in 24-48 hours
o Neutrophils first because they are more numerous in blood, respond more rapidly to chemokines, and
may attach more firmly to adhesion molecules that are rapidly induced on endothelial cells (P and Eselectins); after entering tissues, neutrophils short-lived and undergo apoptosis when monocytes come
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Monocytes survive longer and may proliferate in tissues to become dominant population in chronic
inflammatory reactions
o In certain infections (like those produced by Pseudomonas bacteria), cellular infiltrate dominated by
continuously recruited neutrophils for several days
 In viral infections, lymphocytes may be first cells to arrive
 In some hypersensitivity reactions, eosinophils may be main cell type
o Agents that block TNF (one of major cytokines in leukocyte recruitment) are among most successful
therapeutics for chronic inflammatory diseases
o Antagonists of leukocyte integrins, selectins, and chemokines approved for inflammatory diseases
 Antagonists control inflammation and can compromise ability of treated patients to defend
themselves against microbes
Once leukocytes recruited to site of infection or cell death, they must be activated to perform functions
o Recognition of offending agents delivers signals that activate leukocytes to ingest and destroy offending
agents and amplify inflammatory reaction
o Receptors for microbial products – Toll-like receptors (TLRs) recognize components of different types of
microbes; each type of TLR required for responses to different classes of infectious pathogens
 Different TLRs play essential roles in cellular responses to bacterial lipopolysaccharide (LPS or
endotoxin), other bacterial proteoglycans and lipids, and unmethylated CpG nucleotides (all of
these abundant in bacteria), as well as double-stranded RNA (produced by some viruses)
 TLRs present on cell surface and in endosomal vesicles of leukocytes (and many other cell
types), so they are able to sense products of extracellular and ingested microbes
 Receptors function through receptor-associated kinases to stimulate production of microbicidal
substances and cytokines by leukocytes
 Various other cytoplasmic proteins in leukocytes recognize bacterial peptides and viral RNA
o G protein-coupled receptors found on most types of leukocytes recognize short bacterial peptides
containing N-formylmethionyl residues
 Because all bacterial proteins and few mammalian proteins (only those synthesized in
mitochondria) initiated by N-formylmethionine, receptor enables neutrophils to detect and
respond to bacterial proteins
 Other G protein-coupled receptors recognize chemokines, breakdown products of complement
such as C5a, and lipid mediators, including platelet activating factor, prostaglandins, and
leukotrienes, all of which produced in response to microbes and cell injury
 Binding of ligands, such as microbial products and mediators, to G protein-coupled receptors
induces migration of cells from blood through endothelium and production of microbicidal
substances by activation of respiratory burst
o Receptors for opsonins – leukocytes express receptors for proteins that coat microbes
 Opsonization – process of coating particle in opsonins to target it for ingestion
 Opsonins include antibodies, complement proteins, and lectins
 One of most efficient way sof enhancing phagocytosis of particles is coating particles with IgG
antibodies specific for the particles, which are recognized by high-affinity Fcγ receptor of
phagocytes (FcγRI)
 Components of complement system, especially fragments of complement protein C3, potent
opsonins because they bind to microbes and phagocytes express a receptor (CR1) that
recognizes breakdown products of C3
 Plasma lectins (mainly mannan-binding lectin) bind to bacteria and deliver them to leukocytes
 Binding of opsonized particles to leukocyte Fc or C3 receptors promotes phagocytosis of
particles and activates cells
o Receptors for cytokines – leukocytes express receptors for cytokines that are produced in response to
microbes
 IFN-γ secreted by NK cells reacting to microbes and by antigen-activated T lymphocytes during
adaptive immune responses; major macrophage-activating cytokine
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Recognition of microbes or dead cells by receptors induces leukocyte activation, which results from signaling
pathways triggered in leukocytes, resulting in increases in cytosolic Ca2+ and activation of enzymes such as
protein kinase C and phospholipase A2
o Phagocytosis involves recognition and attachment of particle to be ingested by leukocyte, its engulfment
with subsequent formation of phagocytic vacuole, and killing or degradation of ingested material
 Mannose receptors, scavenger receptors, and receptors for various opsonins function to bind
and ingest microbes
 Macrophage mannose receptor – lectin that binds terminal mannose and fucose residues of
glycoproteins and glycolipids; sugars typically part of molecules found on microbial cell walls
(mammalian glycoproteins and glycolipids contain terminal sialic acid or N-acetylgalactosamine)
 Scavenger receptors – molecules that bind and mediate endocytosis of oxidized or acetylated
LDL particles that can no longer interact with conventional LDL receptor
 Macrophage scavenger receptors bind variety of microbes in addition to LDL particles
 Macrophage integrins (notably Mac-1 [CD11b/CD18]) may bind microbes for
phagocytosis
 Efficiency of phagocytosis greatly enhanced when microbes opsonized for which phagocytes
express high-affinity receptors
o After particle bound to phagocyte receptors, extensions of cytoplasm (pseudopods) flow around it, and
PM pinches off to form vesicle (phagosome) that encloses particle
 Phagosome fuses with lysosomal granule, resulting in discharge of granule’s contents into
phagolysosome; phagocyte may also release granule contents into extracellular space
 Phagocytosis dependent on polymerization of actin filaments, so signals that trigger
phagocytosis are many of same involved in chemotaxis
o Microbial killing accomplished largely by ROS and reactive nitrogen species, mainly derived from NO
 Generation of ROS due to rapid assembly and activation of multicomponent oxidase (NADPH
oxidase, also called phagocyte oxidase), which oxidizes NADPH and, in process, reduces oxygen
to superoxide anion (O2-·)
 In neutrophils, rapid oxidative reaction triggered by activating signals and accompanies
phagocytosis (respiratory burst)
 Phagocyte oxidase is enzyme complex consisting of at least 7 proteins; in resting neutrophils,
different components of enzyme located in PM and cytoplasm
 In response to activating stimuli, cytosolic protein components translocate to
phagosomal membrane, where they assemble and form functional enzyme complex
 ROS produced in lysosome where ingested substances segregated, and cell’s own
organelles protected from harmful effects of ROS
 O2-· converted to H2O2, mostly by spontaneous dismutation; H2O2 not able to efficiently kill
microbes by itself, but aqurophilic granules of neutrophils contain enzyme MPO
(myeloperoxidase) that, in presence of halide such as Cl-, converts H2O2 to hypochlorite (OCl·),
which is a potent antimicrobial agent that destroys microbes by halogenation (in which halide
bound covalently to cellular constituents) or by oxidation of proteins and lipids (lipid
peroxidation)
 H2O2-MPO-halide system is most efficient bactericidal system of neutrophils
 H2O2 also converted to ·OH
 NO produced from arginine by action of NOS; reacts with O2-· to generate highly reactive ONOO·
 Radicals attack and damage lipids, proteins, and nucleic acids of microbes
 Neutrophil granules contain many enzymes such as elastase that contribute to microbial killing
 Microbicidal granule contents include
 Defensins – cationic arginine-rich granule peptides that are toxic to microbes
 Cathelicidins – antimicrobial proteins found in neutrophils and other cells
 Lysozyme – hydrolyzes muramic acid-N-acetylglucosamine bond found in glycopeptide
coat of all bacteria
 Lactoferrin – iron-binding protein present in specific granules
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Major basic protein – cationic protein of eosinophils; limited bactericidal activity, but
cytotoxic to many parasites
 Bactericidal/permeability increasing protein – binds bacterial endotoxin and is
important in defense against some gram-negative bacteria
Leukocytes, especially macrophages, produce growth factors that stimulate proliferation of endothelial cells and
fibroblasts and synthesis of collagen, as well as enzymes that remodel CT
o Macrophages can be activated to respond to microbial products and T-cell cytokines such as IFN-γ and
have strong microbicidal activity (classically activated) or can respond to cytokines such as IL-4 and IL-13
(typically products of TH2 subset of T-cells) and are involved in tissue repair and fibrosis (alternatively
activated)
o Different stimuli activate leukocytes to secrete mediators of inflammation as well as inhibitors of
inflammatory response, and thus serve to both amplify and control reaction
Leukocytes are important causes of injury to normal cells and tissues:
o As part of normal defense reaction against infection, adjacent tissues can suffer collateral damage
o When inflammatory response is inappropriately directed against host tissues
o When host reacts excessively against usually harmless environmental substances (allergies and asthma)
When immune system becomes problem, neutrophils and macrophages release microbicidal and other products
in extracellular space (not just phagolysosome)
o Lysosomal enzymes, present in granules, and ROS and reactive nitrogen species cause damage
o If phagocytes encounter materials not easily ingested (e.g., immune complexes deposited on immovable
flat surfaces), inability of leukocytes to surround and ingest substances (frustrated phagocytosis) triggers
strong activation, and release of large amounts of lysosomal enzymes into extracellular space
o Phagocytosis of membrane-damaging substances, such as urate crystals, may injure membrane of
phagolysosome and lead to release of lysosomal granule contents
Inherited defects in leukocyte adhesion – genetic defects of integrins and selectin-ligands that cause leukocyte
adhesion deficiencies types 1 and 2; major clinical problem is recurrent bacterial infections
Inherited defects in phagolysosome function
o Chédak-Higashi syndrome – autosomal recessive condition characterized by defective fusion of
phagosomes and lysosomes in phagocytes (susceptibility to infections) and abnormalities in
melanocytes (albinism), cells of nervous system (nerve defects), and platelets (bleeding disorders)
 Main leukocyte abnormalities are neutropenia (decreased numbers of neutrophils), defective
degranulation, and delayed microbial killing
 Leukocytes contain giant granules because of aberrant phagolysosome fusion
 Gene associated with this disorder encodes large cytosolic protein (LYST) that regulates
lysosomal trafficking
Inherited defects in microbicidal activity
o Chronic granulomatous disease – characterized by defects in bacterial killing and render patients
susceptible to recurrent bacterial infection
 Results from inherited defects in genes encoding components of phagocyte oxidase, which
generates O2-·
 Most common variants are X-linked defect in one of membrane-bound components and
autosomal recessive defects in genes encoding 2 of cytoplasmic components
 Macrophage-rich chronic inflammatory reaction that tries to control infection when initial
neutrophil defense inadequate, leading to collections of activated macrophages that wall off
microbes, forming aggregates (granulomas)
Acquired deficiencies of leukocyte function – most frequent cause is bone marrow suppression, leading to
decreased production of leukocytes
Mast cells and tissue macrophages – sentinel cells stationed in tissues to rapidly recognize potentially injurious
stimuli and initiate host defense reactions
o Mast cells react to physical trauma, breakdown products of complement, microbial products, and
neuropeptides; mast cells release histamine, leukotrienes, enzymes, and cytokines (TNF, IL-1, and
chemokines)
o Macrophages recognize microbial products and secrete most cytokines important in acute inflammation
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Inflammation declines because mediators of inflammation are produced in rapid bursts, only as long as stimulus
persists, have short half-lives, and are degraded after their release
o Neutrophils die by apoptosis within a few hours after leaving blood
 As inflammation develops, process triggers stop signals that serve to actively terminate reaction
o Switch in type of arachidonic acid metabolite produced, from pro-inflammatory leukotrienes to antiinflammatory lipoxins
o Liberation of anti-inflammatory cytokines, including TGF-β and IL-10, from macrophages and other cells;
production of anti-inflammatory lipid mediators (resolvins and protectins), derived from
polyunsaturated fatty acids, and neural impulses (cholinergic discharge) inhibit production of TNF in
macrophages
Mediators of Inflammation
 Mediators generated either from cells or from plasma proteins – cell-derived mediators normally sequestered in
intracellular granules and can be rapidly secreted by granule exocytosis (e.g., histamine in mast cell granules) or
are synthesized de novo (e.g., prostaglandins, cytokines) in response to stimulus
o Major cell types that produce mediators of acute inflammation are platelets, neutrophils, monocytes,
and mast cells; mesenchymal cells (endothelium, smooth muscle, fibroblasts) and most epithelia can
also be induced to elaborate some mediators
o Plasma-derived mediators (e.g., complement proteins, kinins) produced mainly in liver and present in
circulation as inactive precursors that must be activated, usually be series of proteolytic cleavages, to
acquire biologic properties
 Active mediators produced in response to microbial products, substances released from necrotic cells, and
proteins of complement, kinin, and coagulation systems, which are themselves activated by microbes and
damaged tissues
 One mediator can stimulate release of other mediators – TNF acts on endothelial cells to stimulate production of
IL-1 and many chemokines; secondary mediators may have same or different actions as initial mediators
o Provides mechanisms for amplifying or counteracting initial action of mediator
 Mediators vary in range of cellular targets – can have one or a few target cell types and can have differing
effects on different types of cells
 Once activated and released from cell, most mediators short-lived: quickly decay (arachidonic acid metabolites),
are inactivated by enzymes (kininase inactivates bradykinin), or are scavenged (antioxidants scavenge toxic
oxygen metabolites) or inhibited (complement regulatory proteins break up and degrade activated complement
components)
 Major vasoactive amines are histamine and serotonin – stored as preformed molecules in cells and are among
first mediators to be released during inflammation
o Richest sources of histamine are mast cells present in CT adjacent to blood vessels; histamine also found
in blood basophils and platelets
 Histamine released by mast cell degranulation in response to stimuli such as physical injury
(trauma, cold, heat), binding of antibodies to mast cells (allergic reactions), fragments of
complement (anaphylatoxins C3a and C5a), histamine-releasing proteins derived from
leukocytes, neuropeptides (substance P), and cytokines (IL-1, IL-8)
 Causes dilation of arterioles and increases permeability of venules
 Principal mediator of immediate transient phase of increased vascular permeability, producing
interendothelial gaps in venules
 Vasoactive effects mediated mainly via binding to H1 receptors on microvascular endothelial
cells
o Serotonin – preformed vasoactive mediator present in platelets and certain neuroendocrine cells (GI
tract); release from platelets stimulated when they aggregate after contact with collagen, thrombin,
ADP, and antigen-antibody complexes (link between clotting and inflammation)
 When cells activated by stimuli, membrane arachidonic acid (AA) rapidly converted by actions of enzymes to
produce prostaglandins and leukotrienes
o Biologically active lipid mediators (prostaglandins and leukotrienes) serve as intracellular or extracellular
signals to affect variety of biologic processes, including inflammation and hemostasis
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AA derived from dietary sources or by conversion from essential fatty acid (linoleic acid); normally
esterified in membrane phospholipids
o Stimuli or mediators release AA from membrane phospholipids through action of cellular
phospholipases, mainly phospholipase A2
 Biochemical signals involved in activation of phospholipase A2 include increase in cytoplasmic
Ca2+ and activation of various kinases in response to external stimuli
o AA-derived mediators (eicosanoids) synthesized by cyclooxygenases (which generate prostaglandins)
and lipoxygenases (which produce leukotrienes and lipoxins
o Eicosanoids bind to G-protein-coupled receptors on many cell types and can mediate virtually every step
of inflammation
Prostaglandins – produced by mast cells, macrophages, endothelial cells, and many other cell types; involved in
vascular and systemic reactions of inflammation; produced by actions of 2 cyclooxegenases (constitutively
expressed COX-1 and inducible enzyme COX-2)
o Divided into series based on structural features (PGD-PGH) and subscript numeral that indicates number
of double bonds in compound
o Most important ones in inflammation are PGE2, PGD2, PGF2α, PGI2 (prostacyclin), and TxA2
(thromboxane), each of which derived by action of specific enzyme on intermediate in the pathway
o Some enzymes have restricted tissue distribution – for example, platelets contain enzyme thromboxane
synthetase, hence TxA2 is major product in these cells
 TxA2 (potent platelet-aggregating agent and vasoconstrictor) is unstable and rapidly converted
to inactive form (TxB2)
o Vascular endothelium lacks thromboxane synthetase but possesses prostacyclin synthetase, which leads
to formation of PGI2 and its stable end product (PGF1α)
 Prostacyclin is vasodilator, potent inhibitor of platelet aggregation, and markedly potentiates
permeability-increasing and chemotactic effects of other mediators
 Thromboxane-prostacyclin imbalance implicated as early event in thrombus formation in
coronary and cerebral blood vessels
o PGD2 is major prostaglandin made by mast cells; along with PGE2 (more widely distributed), it causes
vasodilation and increases permeability of post-capillary venules, potentiating edema formation
 PGD2 is chemoattractant for neutrophils
o PGF2α stimulates contraction of uterine and bronchial smooth muscle and small arterioles
o Prostaglandins involved in pathogenesis of pain and fever – PGE2 is hyperalgesic and makes skin
hypersensitive to painful stimuli, such as intradermal injection of suboptimal concentrations of
histamine and bradykinin, and is also involved in cytokine-induced fever during infections
Lipoxygenase enzymes responsible for production of leukotrienes, which are secreted mainly by leukocytes, are
chemoattractants for leukocytes, and have vascular effects
o 5-lipoxygenase (predominant lipoxygenase in neutrophils) converts AA to 5-hydroxyeicosatetraenoic
acid (chemotactic for neutrophils) and is the precursor of leukotrienes
o LTB4 is potent chemotactic agent and activator of neutrophils, causing aggregation and adhesion of cells
to venular endothelium, generation of ROS, and release of lysosomal enzymes
o Cysteinyl-containing leukotrienes C4, D4, and E4 (LTC4, LTD4, and LTE4) cause intense vasoconstriction,
bronchospasm (important in asthma), and increased vascular permeability
 Vascular leakage restricted to venules
o Leukocytes, particularly neutrophils, produce intermediates in lipoxin synthesis that are converted to
lipoxins by platelets interacting with leukocytes
 Principal actions of lipoxins are to inhibit leukocyte recruitment and cellular components of
inflammation; inhibit neutrophil chemotaxis and adhesion to endothelium
 Inverse relationship between production of lipoxin and leukotrienes, so lipoxins endogenous
negative regulators of leukotrienes and play a role in resolution of inflammation
Cyclooxygenase inhibitors include NSAIDs (such as indomethacin and aspirin) that inhibit both COX-1 and COX-2
and thus inhibit prostaglandin synthesis
o Aspirin irreversibly acetylates and inactivates cyclooxygenases
o
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Selective COX-2 inhibitors – COX-2 induced by variety of inflammatory stimuli and is absent from most
tissues under normal resting conditions; COX-1 produced in response to inflammatory stimuli and
constitutively expressed in most tissues
 COX-1 responsible for production of prostaglandins involved in both inflammation and
homeostatic functions (e.g., fluid and electrolyte balance in kidneys, cytoprotection in GI tract),
whereas COX-2 generates prostaglandins that are involved only in inflammatory reactions
 COX-2 inhibitors are anti-inflammatory without having toxicities of nonselective inhibitors, such
as gastric ulceration
 Large clinical trials raise concerns that selective COX-2 inhibitors may increase risk of
cardiovascular and cerebrovascular events, leading to removal of several drugs from market
 COX-2 inhibitors impair endothelial cell production of prostacyclin (vasodilator and inhibitor of
platelet aggregation), while leaving intact COX-1-mediated production by platelets of TxA2
(inducer of platelet aggregation and vasoconstriction)
 Selective COX-2 inhibition tilts balance toward thromboxane and promotes vascular thrombosis,
especially in individuals with other factors that increase risk of thrombosis
Lipoxygenase inhibitors – 5-lipoxygenase not affected by NSAIDs
o Pharmacologic agents that inhibit leukotriene production (e.g., Zileuton) or block leukotriene receptors
(e.g., Montelukast) useful in treatment of asthma
Broad-spectrum inhibitors include corticosteroids – act by reducing transcription of genes encoding COX-2,
phospholipase A2, pro-inflammatory cytokines (such as IL-1 and TNF), and iNOS
Can manipulate inflammatory responses by modifying intake and content of dietary lipids by increasing
consumption of fish oil; polyunsaturated fatty acids in fish oil serve as poor substrates for conversion to active
metabolites by both cyclooxygenase and lipoxygenase pathways but are excellent substrates for production of
anti-inflammatory lipid products (resolvins and protectins)
Platelet activating factor (PAF) – phospholipid-derived mediator; causes platelet aggregation; variety of cell
types can elaborate PAF in both secreted and cell-bound forms
o PAF causes vasoconstriction and bronchoconstriction, and at extremely low concentrations vasodilation
and increased venular permeability (moreso than histamine)
o Causes increased leukocyte adhesion to endothelium by enhancing integrin-medaited leukocyte binding,
chemotaxis, degranulation, and oxidative burst
o PAF boosts synthesis of other mediators, particularly eicosanoids, by leukocytes and other cells
o Synthetic PAF receptor antagonists inhibit inflammation in some experimental models
ROS production dependent on activation of NADPH oxidase system; extracellular release of low levels can
increase expression of chemokines, cytokines, and endothelial leukocyte adhesion molecules, amplifying
inflammatory response
o Endothelial cell damage with resultant increased vascular permeability – adherent neutrophils, when
activated, stimulate production of ROS in endothelial cells
o Injury to other cells (parenchymal cells, RBCs) caused by release of ROSs
o Inactivation of antiproteases, such as α1-antitrypsin, leads to unopposed protease activity with increased
destruction of ECM; in lung, such inhibition of anti-proteases contributes to destruction of elastic
tissues, as in emphysema
o Serum, tissue fluids, and host cells possess antioxidant mechanisms that protect against potentially
harmful oxygen-derived radicals
 Superoxide dismutase (found in or can be activated in variety of cell types), catalase (detoxifies
H2O2), glutathione peroxidase (powerful H2O2 detoxifier), ceruloplasmin (copper-containing
serum protein), and iron-free fraction of transferrin
NO – factor released from endothelial cells that causes vasodilation; also called endothelium-derived relaxing
factor; soluble gas produced by macrophages and some neurons in brain as well as endothelial cells
o Acts in paracrine manner on target cells through induction of cGMP, which initiates series of intracellular
events leading to response, such as relaxation of vascular smooth muscle cells
o Half-life of NO is only seconds, so gas acts only on cells in close proximity to where it was produced
o NO synthesized from L-arginine by nitric oxide synthase (NOS)
 3 types of NOS: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS)
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eNOS and nNOS are constitutively expressed at low levels and can be activated rapidly by
increase in cytoplasmic Ca2+
 iNOS induced when macrophages and other cells activated by cytokines or microbial products
o NO relaxes vascular smooth muscle and promotes vasodilation, contributing to vascular reaction, and is
also inhibitor of cellular component of inflammatory responses
o NO reduces platelet aggregation and adhesion, inhibits several features of mast-cell-induced
inflammation, and inhibits leukocyte recruitment
o NO and its derivatives are microbicidal
o High levels of iNOS-induced NO produced by leukocytes, mainly neutrophils and macrophages, in
response to microbes
Cytokines – proteins produced by many cell types (principally activated lymphocytes and macrophages, but also
endothelial, epithelial, and CT cells) that modulate functions of other cell types
o Products have effects that play important roles in both acute and chronic inflammation
o TNF and IL-1 produced mainly by activated macrophages; secretion can be stimulated by endotoxin and
other microbial products, immune complexes, physical injury, and variety of inflammatory stimuli
 In endothelium, they induce endothelial activation, particularly expression of endothelial
adhesion molecules, synthesis of chemical mediators (including cytokines, chemokines, growth
factors, eicosanoids, and NO), production of enzymes associated with matrix remodeling, and
increases in surface thrombogenicity of endothelium
 TNF augments responses of neutrophils to other stimuli such as bacterial endotoxin
 Production of IL-1 controlled by multi-protein complex (inflammasome) that responds to stimuli
from microbes and dead cells; complex activates proteases that are members of caspase family,
which cleave newly synthesized inactive precursor of IL-1 to biologically active cytokine
 Mutations in genes encoding members of complex are cause of inherited
autoinflammatory syndromes like familial Mediterranean fever
 Mutant proteins either constitutively activate inflammatory caspases or interfere with
negative regulation of enzymatic process; net result is unregulated IL-1 production
 Affected patients present with fever and systemic manifestations of inflammation
without overt provocation
 Some patients can develop amyloidosis
 IL-1 antagonists effective for treating
 Inflammasome complex may be activated by urate crystals in gout (partly mediated by IL-1)
 IL-1 and TNF induce systemic acute-phase responses associated with infection or injury
 TNF regulates energy balance by promoting lipid and protein mobilization and by suppressing
appetite; sustained production of TNF contributes to cachexia
o Chemokines – family of small proteins that act primarily as chemoattractants for specific types of
leukocytes; types of chemokines and receptors classified according to arrangement of conserved
cysteine © residues in mature proteins
 C-X-C chemokines (also called α chemokines) – have one AA residue separating first 2 conserved
cysteine residues; act primarily on neutrophils; IL-8 typical of this group and is secreted by
activated macrophages, endothelial cells, and other cell types, causing activation and
chemotaxis of neutrophils, with limited activity on monocytes and eosinophils
 Most important inducers are microbial products and cytokines, mainly IL-1 and TNF
 C-C chemokines (also called β chemokines) have first 2 conserved cysteine residues adjacent
 Include MCP-1, eotaxin, MIP-1α, and RANTES
 Generally attract monocytes, eosinophils, basophils, and lymphocytes (not neutrophils)
 Eotaxin selectively recruits eosinophils
 C chemokines (also called γ chemokines) – lack 2 (1st and 3rd) of 4 conserved cysteines; relatively
specific for lymphocytes
 CX3C chemokines – contain 3 AAs between 2 cysteines; only known member is fractalkine,
which exists in 2 forms: surface-bound protein can be induced on endothelial cells by
inflammatory cytokines and promotes strong adhesion of monocytes and T cells, and soluble
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form derived by proteolysis of membrane-bound protein (potent chemoattractant activity for
same cells as surface-bound protein)
 Chemokines mediate activities by binding to 7-transmembrane G-protein-coupled receptors that
usually exhibit overlapping ligand specificities, and leukocyte generally express more than one
receptor type
 Certain chemokine receptors (CXCR-4, CCR-5) act as coreceptors for viral envelope glycoprotein
of HIV1 and are thus involved in binding and entry of virus into cells
 Chemokines have 2 main functions
 Stimulate leukocyte recruitment in inflammation
 Control normal migration of cells through various tissues
 Some chemokines produced transiently in response to inflammatory stimuli and promote
recruitment of leukocytes to sites of inflammation
 Some chemokines produced constitutively in tissues and function to organize different cell types
in different anatomic regions of tissues
 Chemokines may be displayed at high concentrations attached to proteoglycans on surface of
endothelial cells and in ECM
 IL-6 – made by macrophages and other cells; involved in local and systemic reactions
 IL-17 – produced mainly by T lymphocytes; promotes neutrophil recruitment
 Cytokines play central roles in chronic inflammation
Neutrophils and monocytes contain lysosomal granules that contribute to inflammatory response
o Neutrophils have 2 main types of granules – both types can fuse with phagocytic vacuoles containing
engulfed material or can be released into extracellular space
 Smaller specific (secondary) granules contain lysozyme, collagenase, gelatinase, lactoferrin,
plasminogen activator, histaminase, and alkaline phosphatase
 Larger azurophil (primary) granules contain myeloperoxidase, lysozyme, defensins, acid
hydrolases, and variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases,
proteinase 3)
o Acid proteases degrade bacteria and debris within phagolysosomes
o Neutral proteases capable of degrading various extracellular components (collagen, basement
membrane, fibrin, elastin, and cartilage) resulting in tissue destruction that accompanies inflammatory
processes
 Can also cleave C3 and C5 complement proteins directly, releasing anaphylatoxins
 Can release kinin-like peptide from kininogen
o Neutrophil elastase degrades virulence factors of bacteria to combat bacterial infections
o Monocytes and macrophages contain acid hydrolases, collagenase, elastase, phospholipase, and
plasminogen activator
o Proteases held in check by system of antiproteases in serum and tissue fluids
 α1-antitrypsin – major inhibitor of neutrophil elastase
 Deficiency can lead to sustained action of leukocyte proteases
 α2-Macroglobulin – antiprotease found in serum and various secretions
Neuropeptides – secreted by sensory nerves and various leukocytes; play role in initiation and propagation of
inflammatory response
o Small peptides, such as substance P and neurokinin A, belong to family of tachykinin neuropeptides
produced in CNS and PNS
o Nerve fibers containing substance P prominent in lung and GI tract; substance P involved in transmission
of pain signals, regulation of blood pressure, stimulation of secretion by endocrine cells, and increasing
vascular permeability
o Sensory neurons produce pro-inflammatory molecules, such as calcitonin-related gene product (link
sensing of painful stimuli to development of protective host responses)
Complement system – functions in both innate and adaptive immunity for defense against microbial pathogens
o In process of complement activation, several cleavage products of complement proteins elaborated that
cause increased vascular permeability, chemotaxis, and opsonization
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Complement proteins present in inactive forms in plasma; many activated to become proteolytic
enzymes that degrade other complement proteins, thus forming enzymatic cascade
o Critical step in complement activation is proteolysis of C3; cleavage of C3 can occur by
 Classical pathway – triggered by fixation of C1 to IgM or IgG that has combined with antigen
 Alternative pathway – triggered by microbial surface molecules (e.g., endotoxin, LPS), complex
polysaccharides, cobra venom, and other substances, in absence of antibody
 Lectin pathway – plasma mannose-binding lectin binds to carbs on microbes and directly
activates C1
o All pathways of cleavage of C3 lead to formation of active C3 convertase, which splits C3 into 2
functionally distinct fragments (C3a and C3b)
o C3a released, and C3b becomes covalently attached to cell or molecule where complement being
activated; more C3b binds to previously generated fragments to form C5 convertase, which cleaves C5
to release C5a and leave C5b attached to cell surface
o C5b binds C6-C9, culminating in formation of MAC, composed of multiple C9 molecules
o Biologic functions of complement system fall into 3 categories
 Inflammation – C3a, C5a, and to a lesser extent C4a are cleavage products of corresponding
complement components that stimulate histamine release from mast cells, thereby increasing
vascular permeability and causing vasodilation
 C3a and C5a are anaphylatoxins because they have effects similar to those of mast cell
mediators that are involved in anaphylaxis
 C5a is powerful chemotactic agent for neutrophils, monocytes, eosinophils, and
basophils; activates lipoxygenase pathway of arachidonic acid metabolism in neutrophils
and monocytes, causing further release of inflammatory mediators
 Phagocytosis – C3b and its cleavage product iC3b (inactive C3b), when fixed to microbial cell
wall, act as opsonins and promote phagocytosis by neutrophils and macrophages, which bear
cell surface receptors for complement fragments
 Cell lysis – deposition of MAC on cells makes them permeable to water and ions and results in
death (lysis) of cells
o C3 and C5 can be cleaved by several proteolytic enzymes present in inflammatory exudate, including
plasmin and lysosomal enzymes released from neutrophils
o Activation of complement tightly controlled by cell-associated and circulating regulatory proteins
 Different regulatory proteins inhibit production of active complement fragments or remove
fragments that deposit on cells
 Regulators expressed on normal host cells and are thus designed to prevent healthy tissues from
being injured at sites of complement activation
 Regulatory proteins can be overwhelmed when large amounts of complement deposited on
host cells and tissues
Intrinsic clotting pathway – series of plasma proteins activated by Hageman factor (factor XII) synthesized by
liver that circulates in inactive form
o Factor XII activated upon contact with negatively charged surfaces (i.e., when vascular permeability
increases and plasma proteins leak into extravascular space and come into contact with collagen, or
when it comes into contact with basement membranes exposed as result of endothelial camage)
o Factor XII activates, exposing active serine center that can subsequently cleave protein substrates and
activate variety of mediator systems
o Inflammation increases production of several coagulation factors, makes endothelial surface prothrombogenic, and inhibits anticoagulation mechanisms
o Thrombin promotes inflammation by engaging receptors (PARs) because they bind multiple trypsin-like
serine proteases in addition to thrombin; receptors are 7-transmembrane G-protein-coupled receptors
expressed on platelets and endothelial and smooth muscle cells (and elsewhere)
o Engagement of PAR-1 by proteases, particularly thrombin, triggers mobilization of P-selectin; production
of PAF and NO; production of chemokines and other cytokines; expression of endothelial adhesion
molecules for leukocyte integrins; induction of cyclooxygenase-2 and production of prostaglandins; and
changes in endothelial shape – promote recruitment of leukocytes and many other reactions of
inflammation
o Because coagulation and inflammation can initiate vicious cycle, interfering with clotting can be strategy
for systemic inflammatory disease seen with severe, disseminated bacterial infections (i.e., treating with
aPC)
 Kinins – vasoactive peptides derived from plasma proteins (kininogens) by action of proteases (kallikreins)
o Kinin and coagulation systems connected because factor XIIa converts plasma prekallikrein into active
proteolytic form (kallikrein), which cleaves plasma glycoprotein precursor (high-molecular-weight
kininogen) to produce bradykinin
o Bradykinin increases vascular permeability and causes contraction of smooth muscle, dilation of blood
vessels, and pain when injected into skin; action of bradykinin short-lived because quickly inactivated by
kininase; any remaining kinin inactivated during passage of plasma through lung by ACE
o Kallikrein is potent activator of factor XII, allowing autocatalytic amplification of initial stimulus
o Kallikrein has chemotactic activity and directly converts C5 to chemoattractant C5a
 Factor XIIa activates fibrinolytic system, which counterbalances clotting by cleaving fibrin
o Kallikrein, as well as plasminogen activator (released from endothelium, leukocytes, and other tissues),
cleaves plasminogen to plasmin
o During inflammation, plasmin cleaves complement protein C3 to produce C3 fragments and degrades
fibrin to form fibrin split products, which may have permeability-inducing properties
o Plasmin can activate factor XII, which can trigger multiple cascades, amplifying response
o Bradykinin, C3a, and C5a (as mediators of increased vascular permeability); C5a (as mediator of
chemotaxis); and thrombin likely to be most important in vivo
o C3a and C5a can be generated by immunologic reactions involving antibodies and complement (classical
pathway), activation of alternative and lectin pathways by microbes in absence of antibodies, and agents
not directly related to immune responses (plasmin, kallikrein, and some serine proteases found in
normal tissue)
o Factor XIIa initiates 4 systems involved in inflammatory response
 Kinin system – produces vasoactive kinins
 Clotting system – induces formation of thrombin, which has inflammatory properties
 Fibrinolytic system – produces plasmin and degrades fibrin to produce fibrinopeptides, which
induce inflammation
 Complement system – produces anaphylatoxins and other mediators
Outcomes of Acute Inflammation
 All acute inflammatory reactions have one of three outcomes
o Complete resolution – inflammatory reactions, once they have succeeded in neutralizing and eliminating
injurious stimulus, end with restoration of site of acute inflammation to normal; usual outcome when
injury limited or short-lived or when there has been little tissue destruction and damaged parenchymal
cells can regenerate; involves removal of cellular debris and microbes by macrophages and resorption of
edema fluid by lymphatics
o Healing by CT replacement (fibrosis) – occurs after substantial tissue destruction, when inflammatory
injury involves tissues incapable of regeneration, or when there is abdundant fibrin exudation in tissue
or serous cavities (pleura, peritoneum) that cannot be adequately cleared
 CT grows into area of damage or exudate, converting it into mass of fibrous tissue (process
called organization)
o Progression of response to chronic inflammation – may follow acute inflammation or response may be
chronic from outset; transition from acute inflammation occurs when acute inflammatory response
cannot be resolved, as result of either persistence of injurious agent or some interference with normal
process of healing
 Bacterial infection of lung may begin as focus of acute inflammation (pneumonia), but failure to
resolve may lead to extensive tissue destruction and formation of cavity in which inflammation
continues to smolder, leading eventually to chronic lung abscess
 Peptic ulcer of duodenum or stomach may persist for months or years and are manifested by
both acute and chronic inflammatory reactions
Morphologic Patterns of Acute Inflammation
 Morphologic hallmarks of all acute inflammatory reactions are dilation of small blood vessels, slowing of blood
flow, and accumulation of leukocytes and fluid in extravascular tissue
o Special morphologic patterns often superimposed on general features, depending on severity of
reaction, specific cause, and particular tissue and site involved
 Serous inflammation – marked by outpouring of thin fluid derived from plasma or from secretions of mesothelial
cells lining peritoneal, pleural, and pericardial cavities
o Accumulation of fluid in cavities is effusion
o Blister on skin is large accumulation of serous fluid, either within or immediately beneath epidermis
 Fibrinous inflammation – with greater increase in vascular permeability, large molecules, such as fibrinogen,
pass vascular barrier, and fibrin formed and deposited in extracellular space
o Fibrinous exudate develops when vascular leaks large or there is local procoagulants stimulus (e.g.,
cancer cells); exudate characteristic of inflammation in lining of body cavities (meninges, pericardium,
and pleura)
o Fibrin appears as eosinophilic meshwork of threads or amorphous coagulum
o Fibrinous exudates may be removed by fibrinolysis and clearing of other debris by macrophages
o If fibrin not removed, over time it may stimulate ingrowth of fibroblasts and blood vessels, leading to
scarring; conversion of fibrinous exudate to scar tissue (organization) in pericardial sac leads to opaque
fibrous thickening of pericardium and epicardium in area of exudation, and if fibrosis extensive,
obliteration of pericardial space
 Suppurative (purulent) inflammation – characterized by production of large amounts of pus or purulent exudate
consisting of neutrophils, liquefactive necrosis, and edema fluid
o Pyogenic bacteria – certain bacteria (e.g., staph) that produce localized suppuration
o Happens in appendicitis
o Abscesses – localized collections of purulent inflammatory tissue caused by suppuration buried in tissue,
organ, or confined space; produced by deep seeding of pyogenic bacteria into tissue
 Have central region that appears as mass of necrotic leukocytes and tissue cells
 Usually a zone of preserved neutrophils around necrotic focus, and outside this region, vascular
dilation and parenchymal and fibroblastic repair
 Abscess may become walled off and ultimately replaced by CT
 Ulcers – local defect (excavation) of surface of organ or tissue produced by sloughing of inflamed necrotic tissue
o Can occur only when tissue necrosis and resultant inflammation exist on or near surface
o Most commonly encountered in mucosa of mouth, stomach, intestines, or genitourinary tract; and skin
and subcutaneous tissue of lower extremities in older persons who have circulatory disturbances that
predispose to extensive ischemic necrosis
o Peptic ulcer of stomach or duodenum – during acute stage, there is intense polymorphonuclear
infiltration and vascular dilation in margins of defect; with chronicity, margins and base of ulcer develop
fibroblastic proliferation, scarring, and accumulation of lymphocytes, macrophages, and plasma cells
Summary of Acute Inflammation
 While phagocytes that reside in all tissues react to invaders (phagocytose), phagocytes and other host cells react
to presence of foreign or abnormal substance by liberating cytokines, lipid messengers, and other mediators of
inflammation
o Some mediators act on small blood vessels in vicinity to promote efflux of plasma and recruitment of
circulating leukocytes to site where offending agent located
o Recruited leukocytes activated by injurious agent and by locally produced mediators, and activated
leukocytes try to remove offending agent by phagocytosis
o As injurious agent eliminated and anti-inflammatory mechanisms become active, process subsides and
host returns to normal state of health
o If injurious agent cannot be quickly eliminated, result may be chronic inflammation
 Vascular phenomena of acute inflammation characterized by increased blood flow to injured area, resulting
mainly from arteriolar dilation and opening of capillary beds induced by mediators such as histamine
o
Increased vascular permeability results in accumulation of protein-rich extravascular fluid, which forms
exudate; plasma proteins leave vessels, most commonly through widened interendothelial cell junctions
of venules
o Redness, heat, and swelling of acute inflammation caused by increased blood flow and edema
o During damage, and in part as result of liberation of prostaglandins, neuropeptides, and cytokines, one
of local symptoms is pain
 Underlying cause determines whether therapeutic goal is to promote or reduce inflammation
o Warm compresses and gargles in case of pharyngitis increase inflammatory response to eliminate
infection faster
o In traumatic injuries and chronic inflammatory diseases, inflammation serves no useful purpose and goal
is to reduce it with application of cold (in trauma) and anti-inflammatory drugs
o At certain locations, such as cornea, it may be desirable to suppress inflammation so corneal
transparency can be maintained
Chronic Inflammation
 Chronic inflammation – inflammation of prolonged duration in which inflammation, tissue injury, and attempts
at repair coexist in varying combinations
o May follow acute inflammation or may begin insidiously as low-grade, smoldering response without any
manifestations of acute reaction – cause of tissue damage in some of most common and disabling
diseases (such as rheumatoid arthritis, atherosclerosis, TB, and pulmonary fibrosis); implicated in
progression of cancer and diseases such as Alzheimer
 Chronic inflammation arises from
o Persistent infections by microorganisms that are difficult to eradicate (mycobacteria, certain viruses,
fungi, and parasites); organisms often evoke immune reaction (delayed-type hypersensitivity)
 Sometimes follows granulomatous reaction
o Immune-mediated inflammatory diseases – caused by excessive and inappropriate activation of immune
system; autoimmune diseases evoke self-perpetuating immune reaction that results in chronic tissue
damage and inflammation
 Chronic inflammation can be result of unregulated immune responses against microbes
(inflammatory bowel disease)
 Allergic diseases, such as bronchial asthma
 Diseases may show morphologic patterns of mixed acute and chronic inflammation because
they are characterized by repeated bouts of inflammation
 Fibrosis may dominate late stages
o Prolonged exposure to potentially toxic agents, either exogenous or endogenous – exposure to
particulate silica (nondegradable inanimate material) that results in silicosis (inflammatory lung disease)
 Atherosclerosis – chronic inflammatory process of arterial wall induced in part by endogenous
toxic plasma lipid components
 Chronic inflammation characterized by
o Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells
o Tissue destruction, induced by persistent offending agent or inflammatory cells
o Attempts at healing by CT replacement of damaged tissue, accomplished by angiogenesis and fibrosis
 Macrophage is dominant cellular player in chronic inflammation; mononuclear phagocyte system
(reticuloendothelial system) consists of closely related cells of bone marrow origin, including blood monocytes
and tissue macrophages
o Half-life of blood monocytes is about 1 day, life span of tissue macrophages is months to years
o Journey from bone marrow stem cell to tissue macrophage regulated by growth and differentiation
factors, cytokines, adhesion molecules, and cellular interactions
o Extravasation of monocytes governed by adhesion molecules and chemical mediators with chemotactic
and activating properties
o Macrophages may be activated by microbial products that engage TLRs and other cellular receptors,
cytokines secreted by sensitized T lymphocytes and NK cells, and other chemical mediators
o Products of activated macrophages sere to eliminate injurious agents such as microbes and initiate
process of repair, and are responsible for much of tissue injury in chronic inflammation
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Activation results in increased levels of lysosomal enzymes and ROS and reactive nitrogen
species, and production of cytokines, growth factors, and other mediators of inflammation
 Some products toxic to microbes and host cells or to ECM; some cause influx of other cell types;
some cause fibroblast proliferation, collagen deposition, and angiogenesis (e.g., growth factors)
o Tissue destruction is one of hallmarks of chronic inflammation because of macrophage products
o Ongoing tissue destruction can activate inflammatory cascade, so features of both acute and chronic
inflammation may coexist in certain circumstances
In short-lived inflammation, if irritant eliminated, macrophages eventually disappear (either dying off or making
their way to lymphatics and lymph nodes)
In chronic inflammation, macrophage accumulation persists, as a result of continuous recruitment from
circulation and local proliferation at site of inflammation
Other cells involved in chronic inflammation include
o Lymphocytes – mobilized in both antibody-mediated and cell-mediated immune reactions
 Antigen-stimulated lymphocytes use various adhesion molecule pairs (selectins, integrins and
their ligands) and chemokines to migrate into inflammatory sites
 Cytokines from activated macrophages (mainly TNF, IL-1, and chemokines) promote leukocyte
recruitment, setting stage for persistence of inflammatory response
 Macrophages display antigens to T cells and produce membrane molecules (costimulators) and
cytokines (IL-12) that stimulate T-cell responses
 Activated T lymphocytes produce cytokines, some of which recruit monocytes from circulation,
and IFN-γ which is powerful activator of macrophages
o Plasma cells – produce antibodies directed either against persistent foreign or self-antigens in
inflammatory site or against altered tissue components
 In some strong chronic inflammatory reactions, accumulation of lymphocytes, APCs, and plasma
cells may assume morphologic features of lymphoid organs, particularly lymph nodes, even
containing well-formed germinal centers (tertiary lymphoid organs); lymphoid organogenesis
often seen in synovium of patients with long-standing RA
o Eosinophils – abundant in immune reactions mediated by IgE and in parasitic infections
 Eotaxin – chemokine important for recruiting eosinophils
 Eosinophils have granules that contain major basic protein (highly cationic protein toxic to
parasites and causes lysis of epithelial cells)
 Contribute to tissue damage in allergies
o Mast cells – widely distributed in CT and participate in acute and chronic inflammatory reactions
 Express receptor FcεRI on surface that binds to Fc portion of IgE antibody, which recognize
antigen, causing cell to degranulate and release mediators (histamine and prostaglandins)
 Occurs during allergic reactions to foods, insect venom, or drugs, and can cause anaphylaxis
 Present in chronic inflammatory reactions; because they secrete many cytokines, they have
ability to both promote and limit inflammatory reactions in different situations
Many forms of chronic inflammation show large numbers of neutrophils, induced either by persistent microbes
or mediators produced by activated macrophages and T lymphocytes
o In osteomyelitis (chronic bacterial infection of bone), neutrophilic exudate can persist for many months
o Neutrophils important in chronic damage induced in lungs by smoking and other irritants
Growth of blood vessels and lymphatic vessels prominent in chronic inflammatory reactions – stimulated by
growth factors (VEGF) produced by macrophages and endothelial cells
Granulomatous inflammation – distinctive pattern of chronic inflammation encountered in limited number of
infectious and some noninfectious conditions
o Immune reactions usually involved in development of granulomas (cellular attempt to contain offending
agent that is difficult to eradicate; strong activation of T lymphocytes leading to macrophage activation,
which can cause injury to normal tissue)
o TB is prototype of granulomatous diseases
o Sarcoidosis, cat-scratch disease, lymphogranuloma inguinale, leprosy, brucellosis, syphilis, some mycotic
infections, berylliosis, reactions of irritant lipids, and some autoimmune diseases included as
granulomatous diseases
o
Recognition of granulomatous pattern in biopsy important because of limited number of possible
conditions that cause it and significance of diagnoses associated with lesions
o Granuloma – focus of chronic inflammation consisting of microscopic aggregation of macrophages that
are transformed into epithelium-like cells, surrounded by collar of mononuclear leukocytes
(lymphocytes and occasionally plasma cells)
 Epithelioid cells have pale pink granular cytoplasm with H&E; indistinct cell boundaries, often
appearing to merge into one another; nucleus less dense than that of lymphocyte, is oval or
elongate, and may show folding of nuclear membrane; frequently fuse to form giant cells in
periphery or sometimes in center of granulomas
 Giant cells have large mass of cytoplasm with 20+ nuclei arranged either peripherally
(Langhans-type giant cell) or haphazardly (foreign-body-type giant cell)
 No known functional difference between 2 types of giant cells
 Older granulomas develop enclosing rim of fibroblasts and CT
 Foreign body granulomas – incited by relatively inert foreign bodies; typically form around
material such as talc (associated with IV drug abuse), sutures, or other fibers that are large
enough to preclude phagocytosis by single macrophage and do not incite any specific
inflammatory or immune response
 Epithelioid cells and giant cells apposed to surface of foreign body
 Foreign material usually identified in center of granuloma, particularly if viewed with
polarized light, where it appears refractile
 Immune granulomas – caused by variety of agents capable of inducing cell-mediated immune
response that produces granulomas usually when inciting agent is poorly degradable or
particulate; macrophages engulf foreign protein antigen, process it, and present peptides to
antigen-specific T lymphocytes, causing their activation
 Responding T cells produce cytokines (IL-2), which activates other T cells, perpetuating
response; also produce IFN-γ, which is important in activating macrophages and
transforming them into epithelioid cells and multinucleate giant cells
 Infection caused by Mycobacterium tuberculosis – granuloma is called tubercle; characterized
by presence of central caseous necrosis (which is rare in other granulomatous diseases)
Systemic Effects of Inflammation
 Acute-phase response – systemic changes associated with acute inflammation; reactions to cytokines whose
production is stimulated by bacterial products (LPS) and other inflammatory stimuli
 Fever – characterized by elevation of body temperature 1-4o C, prominent especially when inflammation
associated with infection
o Produced in response to pyrogens that act by stimulating prostaglandin synthesis in vascular and
perivascular cells of hypothalamus
o LPS and other bacterial products (exogenous pyrogens) stimulate leukocytes to release IL-1 and TNF
(endogenous pyrogens) that increase cyclooxygenases that convert arachidonic acid into prostaglandins
o In hypothalamus, prostaglandins (especially PGE2) stimulate production of neurotransmitters such as
cAMP, which function to reset temperature set point at higher level
o NSAIDs reduce fever by inhibiting prostaglandin synthesis
 Acute-phase proteins – plasma proteins, mostly synthesized in liver, whose plasma concentrations may increase
several hundred-fold as part of response to inflammatory stimuli; examples are CRP, fibrinogen, and SAA protein
o Synthesis by hepatocytes is up-regulated by cytokines, especially IL-6 (for CRP and fibrinogen) and IL-1 or
TNF (for SAA)
o Many acute-phase proteins (CRP and SAA) bind to microbial cell walls and can act as opsonins and fix
complements
o Acute-phase proteins can bind chromatin, aiding in clearing necrotic cell nuclei
o During acute-phase response, SAA protein replaces apolipoprotein A (component of HDL particles),
altering targeting of HDL from liver cells to macrophages, which can use them as source of energyproducing lipids
o Fibrinogen binds to RBCs and causes them to form stacks (rouleaux) that sediment more rapidly at unit
gravity than individual RBCs; why measuring the ESR is test for systemic inflammatory response
o
o
Prolonged production in states of chronic inflammation causes secondary amyloidosis
Elevated serum levels of CRP are marker for increased risk of MI in patients with coronary artery disease
 Inflammation involving atherosclerotic plaques in coronary arteries may predispose to
thrombosis and subsequent infarction, and CRP produced during inflammation
o Hepcidin – iron-regulating peptide whose production increased in acute-phase response; chronically
elevated plasma concentrations of hepcidin reduce availability of iron and are responsible for anemia
associated with chronic inflammation
 Leukocytosis – common feature of inflammatory reactions, especially those induced by bacteria
o Leukemoid reactions – extreme elevations of WBCs
o Occurs initially because of accelerated release of cells from bone marrow postmitotic reserve pool
(caused by cytokines TNF and IL-1) and is associated with rise in number of more immature neutrophils
in blood (shift to left)
o Prolonged infection causes increased production of colony-stimulating factors
o Bone marrow output of leukocytes increased to compensate for loss of cells in inflammatory reaction
o Neutrophilia – increase in blood neutrophil count caused by most bacterial infections
o Lymphocytosis – increase in number of lymphocytes seen in viral infections
o Eosinophilia – increased eosinophils caused by bronchial asthma, allergy, and parasitic infestations
o Leukopenia – decreased number of circulating WBCs caused by typhoid fever, some viruses, rickettsiae,
and certain protozoa; also encountered in infections that overwhelm patients debilitated by
disseminated cancer, rampant TB, or severe alcoholism
 Other manifestations of actue-phase response include increased pulse and blood pressure; decreased sweating
(mainly because of redirection of blood flow from cutaneous to deep vascular beds to minimize heat loss
through skin); rigors (shivering), chills (search for warmth), anorexia, somnolence, and malaise, probably
because of actions of cytokines in brain cells
 Sepsis – large amounts of organisms and LPS in blood stimulate production of enormous quantities of several
cytokines (notably TNF and IL-1)
o High levels of cytokines cause disseminated intravascular coagulation, cardiovascular failure, and
metabolic disturbance (septic shock)
Consequences of Defective or Excessive Inflammation
 Defective inflammation – typically results in increased susceptibility to infections because of lack of innate
immunity; associated with delayed wound healing because inflammation essential for clearing damaged tissues
and debris and provides necessary stimulus to get repair process started
 Excessive inflammation – allergies and autoimmune diseases cause tissue injury mostly from inflammation, not
actual target thereof
o Atherosclerosis, ischemic heart disease, and some neurodegenerative diseases (Alzheimer disease)
o Prolonged inflammation and fibrosis that accompanies it responsible for much of pathology in
infectious, metabolic, and other diseases