Acute and Chronic Inflammation Pathology Chapter 2
Slide 2
Background Inflammation Acute or chronic Depends on the nature
of the stimulus Effectiveness of the initial reaction in
eliminating the stimulus or the damaged tissues Acute inflammation
Rapid in onset (minutes) Short duration (hours or a few days)
Exudation of fluid and plasma proteins (edema) Emigration of
leukocytes (neutrophils)
Slide 3
Background Chronic inflammation May follow acute inflammation
May be insidious in onset Longer duration Presence of lymphocytes
and macrophages Proliferation of blood vessels and fibrosis Tissue
destruction
Slide 4
Historical Highlights Clinical features of inflammation
Egyptian papyrus dated around 3000 BC Celsus Roman writer of the
first century AD First listed the four cardinal signs of
inflammation Rubor (redness) Tumor (swelling) Calor (heat) Dolor
(pain) Signs are typically more prominent in acute
inflammation
Slide 5
Historical Highlights Fifth clinical sign Loss of function
(functio laesa) Added by Rudolf Virchow in the 19th century Sir
Thomas Lewis Studied the inflammatory response in skin Chemical
substances (histamine), mediate the vascular changes of
inflammation
Slide 6
Acute Inflammation Rapid host response Delivers leukocytes and
plasma proteins Sites of infection or tissue injury Three major
components Alterations in vascular caliber Structural changes in
the microvasculature Emigration of the leukocytes
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Stimuli For Acute Inflammation Infections (bacterial, viral,
fungal, parasitic) and microbial toxins Most common and medically
important causes Tissue necrosis Ischemia Trauma, Physical and
chemical injury Foreign bodies Immune reactions
Slide 9
Definitions Exudate Inflammatory extravascular fluid High
protein concentration Specific gravity > 1.020 Usually due to
permeability Transudate Fluid with low protein concentration
(albumin) Specific gravity < 1.012 Permeability usually not
increased (due to a pressure response)
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Definitions Edema Excess interstitial fluid Can be either an
exudate or transudate Pus Purulent exudate Leukocytes (neutrophils)
Debris of dead cells Microbes
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Vascular Changes Vasodilation Earliest manifestations of acute
inflammation Follows a transient constriction of arterioles Lasts a
few seconds First involves the arterioles Leads to opening of new
capillary beds Result is increased blood flow Cause of heat and
redness (erythema) at the site of inflammation Induced by the
action of several mediators Histamine and nitric oxide
Slide 14
Vascular Changes Vasodilation Followed by increased
permeability of the microvasculature Outpouring of protein-rich
fluid into the extravascular tissues Loss of fluid and increased
vessel diameter Leads to slower blood flow, concentration of red
cells in small vessels, and increased viscosity of the blood
Changes result in dilation of small vessels Packed with slowly
moving red cells Stasis
Slide 15
Vascular Changes As stasis progresses. Leukocytes (neutrophils)
accumulate along the vascular endothelium Endothelial cells are
activated by mediators produced at sites of infection and tissue
damage Express increased levels of adhesion molecules Leukocytes
then adhere to the endothelium Migrate through the vascular wall
into the interstitial tissue
Slide 16
Increased Vascular Permeability Hallmark of acute inflammation
Increased vascular permeability Leads to the escape of a
protein-rich exudate into the extravascular tissue Causes
edema
Slide 17
Increased Vascular Permeability Mechanisms Contraction of
endothelial cells Results in increased interendothelial spaces Most
common mechanism of vascular leakage Elicited by histamine,
bradykinin, leukotrienes, the neuropeptide substance P, and many
other mediators Called the immediate transient response Occurs
rapidly after exposure to the mediator Usually short-lived (15-30
minutes)
Slide 18
Increased Vascular Permeability Mechanisms Endothelial injury
Results in endothelial cell necrosis and detachment Direct damage
to the endothelium Transcytosis Increased transport of fluids and
proteins through the endothelial cell
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Responses of the Lymphatics Lymphatics and lymph nodes Filters
and polices the extravascular fluids Normally drain the small
amount of extravascular fluid that leaked out of capillaries
Inflammation Lymph flow is increased and helps drain edema fluid
Accumulates due to increased vascular permeability Lymphatic
vessels proliferate during inflammatory reactions Lymphatics may
become secondarily inflamed (lymphangitis) Draining lymph nodes may
become inflamed (lymphadenitis) Hyperplasia of the lymphoid
follicles Increased numbers of lymphocytes and macrophages
Slide 22
Reactions of Leukocytes in Inflammation Processes involving
leukocytes in inflammation Recruitment from the blood into
extravascular tissues Recognition of microbes and necrotic tissues
Removal of the offending agent
Slide 23
Recruitment of Leukocytes to Sites of Infection and Injury
Extravasation Journey of leukocytes Vessel lumen to the
interstitial tissue Lumen Margination, rolling, and adhesion to
endothelium Migration across endothelium and vessel wall Migration
in the tissues toward a chemotactic stimulus
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Recruitment of Leukocytes to Sites of Infection and Injury
Margination Blood flow slows early in inflammation (stasis)
Hemodynamic conditions change (wall shear stress decreases) More
white cells assume a peripheral position along the endothelial
surface Rolling on the vessel wall Individual and then rows of
leukocytes adhere transiently to the endothelium Detach and bind
again
Slide 26
Recruitment of Leukocytes to Sites of Infection and Injury
Adhere Cells finally come to rest at some point Firmly attach
Resembling pebbles over which a stream runs without disturbing
them
Slide 27
Leukocyte Migration through Endothelium Body Migration of the
leukocytes through the endothelium Transmigration or diapedesis
Occurs mainly in post-capillary venules Chemokines act on the
adherent leukocytes Stimulate the cells to migrate through
interendothelial spaces toward the chemical concentration gradient
Toward the site of injury or infection where the chemokines are
being produced
Slide 28
Leukocyte Migration through Endothelium Body After traversing
the endothelium Leukocytes pierce the basement membrane Enter the
extravascular tissue Cells then migrate toward the chemotactic
gradient Cells accumulate in the extravascular site
Slide 29
Chemotaxis of Leukocytes After exiting the circulation
Leukocytes emigrate in tissues toward the site of injury Chemotaxis
Locomotion oriented along a chemical gradient Chemoattractants
Exogenous substances Bacterial products Lipids Endogenous
substances Chemical mediators Cytokines Components of the
complement system Arachidonic acid (AA)
Slide 30
Chemotaxis of Leukocytes Leukocyte movement Extending filopodia
Pull the back of the cell in the direction of extension Example:
Automobile with front-wheel drive is pulled by the wheels in front
Migrate toward the inflammatory stimulus
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Leukocytic Infiltrate Nature of the leukocyte infiltrate Varies
with the age of the inflammatory response Varies with the type of
stimulus Acute inflammation Neutrophils predominate in the
inflammatory infiltrate During the first 6 to 24 hours Replaced by
monocytes in 24 to 48 hours Survive longer May proliferate in the
tissues Become the dominant population in chronic inflammatory
reactions
Slide 33
Leukocytic Infiltrate Exceptions Pseudomonas bacteria Cellular
infiltrate is dominated by continuously recruited neutrophils for
several days Viral infections Lymphocytes may be the first cells to
arrive Hypersensitivity reactions Eosinophils may be the main cell
type
Slide 34
Recognition of Microbes and Dead Tissues Leukocyte recruitment
to site of infection Must be activated to perform their functions
Recognition of the offending agents Deliver signals Activate the
leukocytes to ingest and destroy the offending agents and amplify
the inflammatory reaction
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Removal of the Offending Agents Leukocyte activation Results
from signaling pathways Increases in cytosolic Ca 2+ Activation of
enzymes Protein kinase C Phospholipase A 2 Functional responses
that are most important for destruction of microbes Phagocytosis
Intracellular killing
Slide 37
Phagocytosis Phagocytosis Involves three sequential steps
Recognition and attachment of the particle to be ingested by the
leukocyte Its engulfment, with subsequent formation of a phagocytic
vacuole Killing or degradation of the ingested material
Slide 38
Engulfment After a particle is bound to phagocyte receptors
Extensions of the cytoplasm (pseudopods) flow around it Plasma
membrane pinches off to form a vesicle (phagosome) Encloses the
particle Fuses with a lysosomal granule Discharge of the granule's
contents into the phagolysosome
Slide 39
Killing and Degradation Final step in the elimination of
infectious agents and necrotic cells Occurs within neutrophils and
macrophages Microbial killing is accomplished largely by reactive
oxygen species and reactive nitrogen species
Slide 40
Microbial killing Can also occur through the action of other
substances in leukocyte granules Granules contain many enzymes
Elastase Defensins Cationic arginine-rich granule peptides that are
toxic to microbes Cathelicidins Antimicrobial proteins found in
neutrophils and other cells Lysozyme Hydrolyzes the muramic
acid-N-acetylglucosamine bond, found in the glycopeptide coat of
all bacteria
Slide 41
Microbial killing Leukocyte granules Granules contain many
enzymes Lactoferrin Iron-binding protein present in specific
granules Major basic protein Cationic protein of eosinophils
Limited bactericidal activity Cytotoxic to many parasites
Bactericidal/permeability increasing protein Binds bacterial
endotoxin Believed to be important in defense against some gram-
negative bacteria
Slide 42
Functional Responses of Activated Leukocytes Leukocytes play
several other roles in host defense Produce a number of growth
factors Stimulate the proliferation of endothelial cells and
fibroblasts Stimulate the synthesis of collagen Stimulate enzymes
that remodel connective tissues These products drive the process of
repair after tissue injury
Slide 43
Release of Leukocyte Products and Leukocyte-Mediated Tissue
Injury Leukocytes are important causes of injury to normal cells
and tissues under several circumstances Part of a normal defense
reaction against infectious microbes Infections that are difficult
to eradicate (TB) and certain viral diseases Prolonged host
response contributes more to the pathology than does the microbe
itself Inappropriately directed inflammatory response Against host
tissues, as in certain autoimmune diseases Excessive host reaction
Against usually harmless environmental substances Allergic
diseases, including asthma
Slide 44
Defects in Leukocyte Function Inherited and acquired Lead to
increased vulnerability to infections Impairments of leukocyte
function Inherited defects in leukocyte adhesion Inherited defects
in phagolysosome function Chdiak-Higashi syndrome Autosomal
recessive condition Characterized by defective fusion of phagosomes
and lysosomes in phagocytes Causing susceptibility to
infections
Slide 45
Defects in Leukocyte Function Impairments of leukocyte function
Inherited defects in leukocyte adhesion Inherited defects in
phagolysosome function Chdiak-Higashi syndrome Abnormalities in
melanocytes (leading to albinism) Cells of the nervous system
(associated with nerve defects) Platelets (causing bleeding
disorders) Leukocyte abnormalities Neutropenia (decreased numbers
of neutrophils) Defective degranulation Delayed microbial
killing
Slide 46
Defects in Leukocyte Function Impairments of leukocyte function
Inherited defects in microbicidal activity Chronic granulomatous
disease (group of congenital diseases) Characterized by defects in
bacterial killing Render patients susceptible to recurrent
bacterial infection Inherited defects in the genes encoding
components of phagocyte oxidase Name of this disease comes from the
macrophage-rich chronic inflammatory reaction Tries to control the
infection when the initial neutrophil defense is inadequate Leads
to collections of activated macrophages that wall off the microbes
Aggregates called granulomas
Slide 47
Defects in Leukocyte Function Impairments of leukocyte function
Acquired deficiencies Most frequent cause of leukocyte defects Bone
marrow suppression Decreased production of leukocytes Seen
following therapies for cancer (radiation and chemotherapy) Seen
when the marrow space is compromised by tumors Arise in the marrow
Leukemias Metastatic from other sites
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Acute and Chronic Inflammation PART 2
Slide 49
Mediators of Inflammation Mediators are generated either from
cells or from plasma proteins Cell-derived mediators Normally
sequestered in intracellular granules Can be rapidly secreted by
granule exocytosis Histamine in mast cell granules Synthesized de
novo in response to a stimulus Prostaglandins, cytokines
Slide 50
Mediators of Inflammation Cells that produce mediators
Platelets, neutrophils, monocytes/macrophages, and mast cells
Mesenchymal cells (endothelium, smooth muscle, fibroblasts) Most
epithelia Plasma-derived mediators Complement proteins, kinins
Produced mainly in the liver Present in the circulation as inactive
precursors Must be activated to acquire their biologic
properties
Slide 51
Mediators of Inflammation Active mediators Produced in response
to various stimuli Microbial products Substances released from
necrotic cells Proteins of the complement, kinin, and coagulation
systems Activated by microbes and damaged tissues Ensures that
inflammation is normally triggered only when and where it is
needed
Slide 52
Mediators of Inflammation Mediators are short-lived Once
activated and released from the cell Quickly decay Arachidonic acid
metabolites Inactivated by enzymes Kininase inactivates bradykinin
Otherwise scavenged or inhibited Antioxidants scavenge toxic oxygen
metabolites Inhibited: complement regulatory proteins break up and
degrade activated complement components
Slide 53
Cell-Derived Mediators Vasoactive amines Two major vasoactive
amines Histamine and Serotonin Stored as preformed molecules in
cells and are Among the first mediators to be released during
inflammation
Slide 54
Histamine Richest sources Mast cells Normally present in the
connective tissue adjacent to blood vessels Found in blood
basophils and platelets Present in mast cell granules
Slide 55
Histamine Released by mast cell degranulation in response to:
Physical injury such as trauma, cold, or heat Binding of antibodies
to mast cells (allergic reactions) Fragments of complement called
anaphylatoxins C3a and C5a Histamine-releasing proteins derived
from leukocytes Neuropeptides (substance P) Cytokines (IL-1,
IL-8)
Slide 56
Histamine Causes dilation of arterioles Increases the
permeability of venules Considered to be the principal mediator of
the immediate transient phase of increased vascular permeability
Producing interendothelial gaps in venules
Slide 57
Serotonin Preformed vasoactive mediator Actions similar to
those of histamine Present in platelets Stimulated when platelets
aggregate After contact with collagen, thrombin, adenosine
diphosphate, and antigen-antibody complexes Platelet release
reaction Key component of coagulation Present in certain
neuroendocrine cells Gastrointestinal tract
Slide 58
Arachidonic Acid (AA) Metabolites Prostaglandins, Leukotrienes,
and Lipoxins Arachidonic acid 20-carbon polyunsaturated fatty acid
Derived from dietary sources Conversion from the essential fatty
acid linoleic acid
Slide 59
Arachidonic Acid (AA) Metabolites Arachidonic acid Does not
occur free in the cell Normally esterified in membrane
phospholipids Mechanical, chemical, and physical stimuli Release AA
from membrane phospholipids through the action of cellular
phospholipases Phospholipase A 2
Slide 60
Arachidonic Acid (AA) Metabolites AA-derived mediators
(eicosanoids) Synthesized by two major classes of enzymes
Cyclooxygenases Generate prostaglandins Lipoxygenases Produce
leukotrienes and lipoxins Bind to G protein-coupled receptors on
many cell types Can mediate virtually every step of
inflammation
Slide 61
Prostaglandins Produced by mast cells, macrophages, endothelial
cells, and many others Involved in the vascular and systemic
reactions of inflammation Produced by the actions of two
cyclooxgenases Constitutively expressed COX-1 Inducible enzyme
COX-2
Slide 62
Prostaglandins Divided into series based on structural features
Coded by a letter PGD, PGE, PGF, PGG, and PGH Subscript numeral 1,
2 Indicates the number of double bonds in the compound
Slide 63
Prostaglandins Most important ones in inflammation PGE 2, PGD
2, PGF 2 , PGI 2 (prostacyclin), and TxA 2 (thromboxane)
Prostacyclin Vasodilator Potent inhibitor of platelet aggregation
Markedly potentiates the permeability- increasing and chemotactic
effects of other mediators
Slide 64
Prostaglandins PGD 2 Major prostaglandin made by mast cells
Along with PGE 2 (which is more widely distributed) Causes
vasodilation Increases the permeability of post-capillary venules
Potentiating edema formation PGF 2 Stimulates the contraction of
uterine and bronchial smooth muscle and small arterioles
Slide 65
Prostaglandins PGD 2 Chemoattractant for neutrophils PGE 2
Hyperalgesic Makes skin hypersensitive to painful stimuli Involved
in cytokine-induced fever during infections
Slide 66
Leukotrienes Produced by lipoxygenase enzymes Secreted mainly
by leukocytes Chemoattractants for leukocytes Vascular effects
Slide 67
Leukotrienes Three different lipoxygenases 5-lipoxygenase
Predominant one in neutrophils Converts AA to
5-hydroxyeicosatetraenoic acid Chemotactic for neutrophils
Precursor of the leukotrienes
Slide 68
Leukotrienes Three different lipoxygenases LTB 4 Potent
chemotactic agent and activator of neutrophils Causes aggregation
and adhesion of the cells to venular endothelium Generation of ROS
Releases lysosomal enzymes
Slide 69
Leukotrienes Three different lipoxygenases Cysteinyl-containing
leukotrienes C 4, D 4, and E 4 (LTC 4, LTD 4, LTE 4 ) Intense
vasoconstriction, bronchospasm and increased vascular
permeability
Slide 70
Lipoxins Generated from AA by the lipoxygenase pathway
Inhibitors of inflammation Two cell populations are required for
their biosynthesis Leukocytes (esp. neutrophils) Produce
intermediates in lipoxin synthesis Converted to lipoxins by
platelets interacting with the leukocytes
Slide 71
Lipoxins Principal actions of lipoxins Inhibit leukocyte
recruitment and the cellular components of inflammation Inhibit
neutrophil chemotaxis and adhesion to endothelium Inverse
relationship between the production of lipoxin and leukotrienes
Suggests that lipoxins may be endogenous negative regulators of
leukotrienes May thus play a role in the resolution of
inflammation
Slide 72
Inhibition of Eicosanoid Synthesis Anti-inflammatory drugs work
by inhibiting the synthesis of eicosanoids Cyclooxygenase
inhibitors Aspirin Non-steroidal anti-inflammatory drugs
Indomethacin Inhibit both COX-1 and COX-2 Inhibit prostaglandin
synthesis
Slide 73
Inhibition of Eicosanoid Synthesis Lipoxygenase inhibitors
5-lipoxygenase is not affected by NSAIDs Inhibit leukotriene
production (Zileuton) Block leukotriene receptors (Montelukast)
Useful in the treatment of asthma Broad-spectrum inhibitors
Corticosteroids Powerful anti-inflammatory agents Reduces the
transcription of genes encoding COX-2, phospholipase A 2,
pro-inflammatory cytokines (such as IL-1 and TNF)
Slide 74
Inhibition of Eicosanoid Synthesis Modify the intake and
content of dietary lipids Increasing the consumption of fish oil
Polyunsaturated fatty acids in fish oil Serve as poor substrates
for conversion to active metabolites Excellent substrates for the
production of anti-inflammatory lipid products Resolvins and
protectins
Slide 75
Platelet-Activating Factor (PAF) Phospholipid-derived mediator
Causes platelet aggregation Known to have multiple inflammatory
effects Variety of cell types can elaborate PAF Platelets,
basophils, mast cells, neutrophils, macrophages, and endothelial
cells
Slide 76
Platelet-Activating Factor (PAF) Causes vasoconstriction and
bronchoconstriction At extremely low concentrations Induces
vasodilation Increased venular permeability Causes increased
leukocyte adhesion, chemotaxis, degranulation, and the oxidative
burst Boosts the synthesis of other mediators (eicosanoids)
Slide 77
Reactive Oxygen Species Oxygen-derived free radicals May be
released extracellularly from leukocytes After exposure to
microbes, chemokines, and immune complexes Following a phagocytic
challenge Production is dependent on the activation of the NADPH
oxidase system Superoxide anion, hydrogen peroxide, and hydroxyl
radical Major species produced within cells Combine with nitric
oxide to form reactive nitrogen species
Slide 78
Reactive Oxygen Species Implicated in responses in inflammation
Endothelial cell damage, with resultant increased vascular
permeability Injury to other cell types (parenchymal cells, red
blood cells) Inactivation of antiproteases ( 1 -antitrypsin)
Slide 79
Antioxidants Superoxide dismutase Found in or can be activated
in a variety of cell types Catalase Detoxifies H 2 O 2 Glutathione
peroxidase Powerful H 2 O 2 detoxifier Ceruloplasmin
Copper-containing serum protein Serum transferrin Iron-free
fraction
Slide 80
Nitric Oxide (NO) Discovered as a factor released from
endothelial cells Caused vasodilation Called endothelium-derived
relaxing factor Soluble gas Produced by endothelial cells,
macrophages and some neurons Acts in a paracrine manner on target
cells Relaxation of vascular smooth muscle cells In vivo half-life
of NO is only seconds Gas acts only on cells in close proximity to
where it is produced
Slide 81
Nitric Oxide (NO) Has dual actions in inflammation Relaxes
vascular smooth muscle Promotes vasodilation Inhibitor of the
cellular component of inflammatory responses
Slide 82
Nitric Oxide (NO) Reduces platelet aggregation and adhesion
Inhibits several features of mast cell- induced inflammation
Inhibits leukocyte recruitment NO and its derivatives are
microbicidal NO is a mediator of host defense against
infection
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Cytokines and Chemokines Cytokines Proteins produced by many
cell types Principally activated lymphocytes and macrophages Also
endothelial, epithelial, and connective tissue cells Involved in
cellular immune responses
Slide 85
Cytokines and Chemokines Tumor Necrosis Factor and
Interleukin-1 Major cytokines that mediate inflammation Produced
mainly by activated macrophages Secretion of TNF and IL-1
Stimulated by endotoxin and other microbial products, immune
complexes, physical injury, and a variety of inflammatory
stimuli
Slide 86
Cytokines and Chemokines Tumor Necrosis Factor and
Interleukin-1 Endothelium Induce a spectrum of changes Referred to
as endothelial activation Induce the expression of endothelial
adhesion molecules Synthesis of chemical mediators, including other
cytokines, chemokines, growth factors, eicosanoids, and NO
Production of enzymes associated with matrix remodeling Increases
in the surface thrombogenicity of the endothelium Augments
responses of neutrophils to other stimuli Bacterial endotoxin
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Tumor Necrosis Factor and IL-1 Induce the systemic acute-phase
responses Associated with infection or injury Regulates energy
balance by promoting lipid and protein mobilization and by
suppressing appetite Sustained production contributes to cachexia
Pathologic state characterized by weight loss and anorexia
Accompanies some chronic infections and neoplastic diseases
Slide 89
Chemokines Family of small (8 to 10 kD) proteins Act primarily
as chemoattractants for specific types of leukocytes 40 different
chemokines 20 different receptors Two main functions Stimulate
leukocyte recruitment in inflammation Control the normal migration
of cells through various tissues
Slide 90
Chemokines Classified into four major groups According to the
arrangement of the conserved cysteine (C) residues in the mature
proteins C-X-C chemokines ( chemokines) One amino acid residue
separating the first two conserved cysteine residues Act primarily
on neutrophils IL-8 is typical of this group Secreted by activated
macrophages, endothelial cells, and other cell types Causes
activation and chemotaxis of neutrophils, with limited activity on
monocytes and eosinophils Most important inducers are microbial
products and other cytokines, mainly IL-1 and TNF
Slide 91
Chemokines Classified into four major groups C-C chemokines (
chemokines) First two conserved cysteine residues adjacent
Generally attract monocytes, eosinophils, basophils, and
lymphocytes but not neutrophils C chemokines ( chemokines) Lack two
(the first and third) of the four conserved cysteines Lymphotactin
Relatively specific for lymphocytes
Slide 92
Chemokines Classified into four major groups CX3C chemokines
Contain three amino acids between the two cysteines Fractalkine Two
forms Cell surface-bound protein Soluble form
Slide 93
Lysosomal Constituents of Leukocytes Neutrophils and monocytes
contain lysosomal granules Neutrophils have two main types of
granules Smaller specific (or secondary) granules Contain lysozyme,
collagenase, gelatinase, lactoferrin, plasminogen activator,
histaminase, and alkaline phosphatase Larger azurophil (or primary)
granules Contain myeloperoxidase, bactericidal factors (lysozyme,
defensins), acid hydrolases, and a variety of neutral
proteases
Slide 94
Lysosomal Constituents of Leukocytes Neutrophils have two main
types of granules Both types of granules can fuse with phagocytic
vacuoles containing engulfed material Granule contents can be
released into the extracellular space
Slide 95
Neuropeptides Secreted by sensory nerves and various leukocytes
Play a role in the initiation and propagation of inflammation
Substance P and neurokinin A Family of tachykinin neuropeptides
Produced in the central and peripheral nervous systems Biologic
functions Transmission of pain signals Regulation of blood pressure
Stimulation of secretion by endocrine cells Increasing vascular
permeability
Slide 96
Plasma Protein-Derived Mediators Three interrelated systems:
the complement, kinin, and clotting systems Complement System
Consists of more than 20 proteins Numbered C1 through C9 Functions
in both innate and adaptive immunity for defense against microbial
pathogens Several cleavage products of complement proteins are
elaborated Cause increased vascular permeability, chemotaxis, and
opsonization Critical step in complement activation Proteolysis of
the third (and most abundant) component, C3
Slide 97
Complement System Functionally divided into three general
categories Inflammation C3a, C5a, and, to a lesser extent, C4a are
cleavage products of the corresponding complement Stimulate
histamine release from mast cells Increase vascular permeability
and cause vasodilation Called anaphylatoxins C5a Powerful
chemotactic agent for neutrophils, monocytes, eosinophils, and
basophils Activates the lipoxygenase pathway of AA metabolism in
neutrophils and monocytes Causes further release of inflammatory
mediators
Slide 98
Complement System Functionally divided into three general
categories Phagocytosis C3b and its cleavage product iC3b (inactive
C3b) When fixed to a microbial cell wall, act as opsonins Promote
phagocytosis by neutrophils and macrophages Cell lysis Deposition
of the MAC on cells Cells permeable to water and ions Results in
death (lysis) of the cells
Slide 99
Complement System C3a and C5a Most important inflammatory
mediators Can be cleaved by several proteolytic enzymes present
within the inflammatory exudate Include plasmin and lysosomal
enzymes released from neutrophils Initiate a self-perpetuating
cycle of neutrophil recruitment
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Coagulation and Kinin Systems Culminate in the activation of
thrombin and the formation of fibrin Intrinsic clotting pathway
Series of plasma proteins Activated by Hageman factor (factor XII)
Protein synthesized by the liver that circulates in an inactive
form Activated upon contact with negatively charged surfaces
Slide 102
Kinins Vasoactive peptides Derived from plasma proteins
(kininogens) Action of specific proteases (kallikreins) Active form
of factor XII (factor XIIa) Converts plasma prekallikrein into an
active proteolytic form (kallikrein) Cleaves a plasma glycoprotein
precursor high-molecular-weight kininogen, to produce bradykinin
Bradykinin Increases vascular permeability Causes contraction of
smooth muscle Dilation of blood vessels Pain when injected into the
skin Short-lived---quickly inactivated by an enzyme called
kininase
Slide 103
Kinins At the same time factor XIIa is inducing fibrin clot
formation, it activates the fibrinolytic system Cascade
counterbalances clotting by cleaving fibrin Solubilizing the clot
Kallikrein Cleaves plasminogen Plasma protein that binds to the
evolving fibrin clot to generate plasmin Multifunctional
protease
Slide 104
Kinins Fibrinolytic system Primary function of plasmin Lyse
fibrin clots Cleaves the complement protein C3 to produce C3
fragments Degrades fibrin to form fibrin split products Activate
Hageman factor Trigger multiple cascades
Slide 105
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Summary Bradykinin, C3a, and C5a Mediators of increased
vascular permeability C5a Mediator of chemotaxis Thrombin Effects
on endothelial cells and many other cell types
Slide 107
Summary C3a and C5a Generated by several types of reactions
Immunologic reactions, involving antibodies and complement (the
classical pathway) Activation of the alternative and lectin
complement pathways by microbes, in the absence of antibodies
Agents not directly related to immune responses Plasmin,
kallikrein, and some serine proteases
Slide 108
Summary Activated Hageman factor (factor XIIa) Initiates four
systems (inflammatory response) Kinin system Produces vasoactive
kinins Clotting system Induces formation of thrombin Fibrinolytic
system Produces plasmin Degrades fibrin to produce fibrinopeptides
Complement system Produces anaphylatoxins and other mediators
Slide 109
Acute and Chronic Inflammation PART 3
Slide 110
Outcomes of Acute Inflammation Variables that may modify the
basic process of inflammation Nature and intensity of the injury
Site and tissue affected Responsiveness of the host
Slide 111
Outcomes of Acute Inflammation Inflammatory reactions--outcomes
Complete resolution Restoration of site of acute inflammation to
normal Usual outcome Injury is limited or short-lived Little tissue
destruction and the damaged parenchymal cells can regenerate
Removal of cellular debris and microbes by macrophages Resorption
of edema fluid by lymphatics
Slide 112
Outcomes of Acute Inflammation Inflammatory reactions--outcomes
Healing by connective tissue replacement Fibrosis Occurs after
substantial tissue destruction Inflammatory injury involves tissues
that are incapable of regeneration Abundant fibrin exudation in
tissue or serous cavities that cannot be adequately cleared
Connective tissue grows into the area of damage Converts it into a
mass of fibrous tissue Organization
Slide 113
Outcomes of Acute Inflammation Inflammatory reactions--outcomes
Progression of the response to chronic inflammation May follow
acute inflammation Response may be chronic from the onset
Slide 114
Outcomes of Acute Inflammation Progression of the response to
chronic inflammation Acute to chronic transition Acute inflammatory
response cannot be resolved Persistence of injurious agent
Interference with normal process of healing Bacterial infection of
the lung Focus of acute inflammation (pneumonia) Extensive tissue
destruction and formation of a cavity Chronic lung abscess
Slide 115
Slide 116
Morphologic Patterns of Acute Inflammation Morphologic
hallmarks of acute inflammation Dilation of small blood vessels
Slowing of blood flow Accumulation of leukocytes and fluid
Extravascular tissue
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Serous Inflammation Marked by outpouring of thin fluid Derived
from plasma/secretions of mesothelial cells Peritoneal, pleural,
and pericardial cavities Accumulation of fluid in these cavities
Effusion Skin blister Burn or viral infection Large accumulation of
serous fluid
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Fibrinous Inflammation Fibrinous exudate Vascular leaks are
large Local procoagulant stimulus (e.g., cancer cells)
Characteristic of inflammation Lining of body cavities Meninges,
pericardium and pleura
Slide 129
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Fibrinous Inflammation Fibrinous exudate Microscopic
examination Fibrin appears as an eosinophilic meshwork of threads
Amorphous coagulum Removed by fibrinolysis and clearing of other
debris by macrophages
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Fibrinous Inflammation Fibrinous exudate If fibrin is not
removed Stimulates ingrowth of fibroblasts and blood vessels Leads
to scarring Conversion of the fibrinous exudate to scar tissue
(organization) Pericardial sac Opaque fibrous thickening of the
pericardium and epicardium Obliteration of the pericardial
space
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Suppurative Inflammation Large amounts of purulent exudate
Neutrophils, liquefactive necrosis, and edema fluid Bacteria (e.g.,
staphylococci) produce this localized suppuration Pyogenic
(pus-producing) bacteria Example Acute appendicitis
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Suppurative Inflammation Abscesses Localized collections of
purulent inflammatory tissue Suppuration buried in a tissue, an
organ, or a confined space Produced by deep seeding of pyogenic
bacteria into a tissue
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Suppurative Inflammation Abscesses Central region Appears as
mass of necrotic leukocytes and tissue cells Necrotic focus Around
it---zone of preserved neutrophils Outside it---vascular dilation
and parenchymal and fibroblastic proliferation
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Ulcers Local defect, or excavation, of the surface of an organ
or tissue Produced by the sloughing (shedding) of inflamed necrotic
tissue Most commonly encountered Mucosa of the mouth, stomach,
intestines, or genitourinary tract Skin and subcutaneous tissue of
the lower extremities Older persons who have circulatory
disturbances
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Summary of Inflammation Vascular phenomena of acute
inflammation Characterized by increased blood flow to the injured
area Results mainly from arteriolar dilation and opening of
capillary beds Induced by mediators such as histamine
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Summary of Inflammation Vascular phenomena of acute
inflammation Increased vascular permeability Accumulation of
protein-rich extravascular fluid (exudate) Plasma proteins leave
the vessels (widened interendothelial cell junctions of the
venules) Redness (rubor), warmth (calor), and swelling (tumor)
Increased blood flow and edema
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Summary of Inflammation Vascular phenomena of acute
inflammation Circulating leukocytes Adhere to the endothelium via
adhesion molecules Traverse the endothelium Migrate to the site of
injury under the influence of chemotactic agents Activated
leukocytes release toxic metabolites and proteases extracellularly
Causes tissue damage Prostaglandins, neuropeptides, and cytokines
released Local symptom---pain (dolor)
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Chronic Inflammation Inflammation of prolonged duration Weeks
or months May follow acute inflammation May begin insidiously
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Causes of Chronic Inflammation Persistent infections by
microorganisms Mycobacteria, and certain viruses, fungi, and
parasites Immune reaction (delayed-type hypersensitivity)
Immune-mediated inflammatory diseases Autoimmune diseases
Atherosclerosis Chronic inflammatory process of the arterial wall
Induced by endogenous toxic plasma lipid components
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Morphology of Chronic Inflammation Infiltration with
mononuclear cells Macrophages, lymphocytes, and plasma cells Tissue
destruction Induced by the persistent offending agent or by the
inflammatory cells Proliferation of small blood vessels
Angiogenesis Fibrosis
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Macrophages in Chronic Inflammation Component of the
mononuclear phagocyte system Also known as the reticuloendothelial
system Consists of closely related cells of bone marrow origin
Blood monocytes Tissue macrophages
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Macrophages in Chronic Inflammation Component of the
mononuclear phagocyte system Tissue macrophages Diffusely scattered
in the connective tissue Liver (Kupffer cells) Spleen Lymph nodes
(sinus histiocytes) Lungs (alveolar macrophages) Central nervous
system (microglia)
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Macrophages in Chronic Inflammation Mononuclear phagocytes
Arise from a common precursor in the bone marrow Gives rise to
blood monocytes From the blood, monocytes migrate into tissues
Half-life of blood monocytes is about 1 day Differentiate into
macrophages Life span of tissue macrophages is several months or
years
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Macrophages in Chronic Inflammation Monocytes emigrate into
extravascular tissues Early in acute inflammation Within 48
hours--predominant cell type When it reaches the extravascular
tissue Undergoes transformation into the macrophage Activated by a
variety of stimuli Microbial products Cytokines Other chemical
mediators
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Macrophages in Chronic Inflammation Products of activated
macrophages Serve to eliminate injurious agents (microbes) Initiate
the process of repair Responsible for tissue injury in chronic
inflammation Activation of macrophages Increased levels of
lysosomal enzymes and reactive oxygen and nitrogen species
Production of cytokines, growth factors, and other mediators of
inflammation Tissue destruction Hallmark of chronic
inflammation
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Other Cells in Chronic Inflammation Lymphocytes Plasma cells
Develop from activated B lymphocytes Produce antibodies Directed
either against persistent foreign or self antigens
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Other Cells in Chronic Inflammation Eosinophils Abundant in
immune reactions Mediated by IgE Parasitic infections Chemokine for
eosinophil recruitment Eotaxin Granules that contain major basic
protein Highly cationic protein that is toxic to parasites Causes
lysis of mammalian epithelial cells Benefit in controlling
parasitic infections Contribute to tissue damage in immune
reactions Allergies
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Other Cells in Chronic Inflammation Mast cells Widely
distributed in connective tissues Participate in acute and chronic
inflammatory reactions Degranulation and release of mediators
Histamine and prostaglandins Allergic reactions to foods, insect
venom, or drugs Catastrophic results (e.g. anaphylactic shock)
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Granulomatous Inflammation Distinctive pattern of chronic
inflammation Cellular attempt to contain an offending agent that is
difficult to eradicate Strong activation of T lymphocytes Leading
to macrophage activation Cause injury to normal tissues
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Granulomatous Inflammation Most commonly seen Tuberculosis
Sarcoidosis Cat-scratch disease Lymphogranuloma inguinale Leprosy
Brucellosis Syphilis Mycotic infections Berylliosis
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Granuloma Focus of chronic inflammation Consists of a
microscopic aggregation of macrophages Transformed into
epithelium-like cells Surrounded by a collar of mononuclear
leukocytes Lymphocytes and occasionally plasma cells
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Granuloma Epithelioid cells Pale pink granular cytoplasm
Indistinct cell boundaries Fuse to form giant cells Periphery or
center of granulomas May attain diameters of 40 to 50 m
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Granuloma Two types of granulomas Foreign body granulomas
Incited by relatively inert foreign bodies Form around material
Talc (IV drug abuse) Sutures Foreign material can be identified in
the center of the granuloma Refractile
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Granuloma Immune granulomas Caused by a variety of agents that
are capable of inducing a cell-mediated immune response Produces
granulomas usually when the inciting agent is poorly degradable or
particulate Prototype is caused by infection with Mycobacterium
tuberculosis Granuloma is referred to as a tubercle Presence of
central caseous necrosis rare in other granulomatous diseases
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Systemic Effects of Inflammation Collectively called the
acute-phase response Also known as the systemic inflammatory
response syndrome Reactions to cytokines whose production is
stimulated by bacterial products Consists of several clinical and
pathologic changes Fever Elevation of body temperature (1 to 4C)
One of the most prominent manifestations Produced in response to
substances called pyrogens
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Systemic Effects of Inflammation Consists of several clinical
and pathologic changes Acute-phase proteins Plasma proteins
Synthesized in the liver Concentrate in the plasma in response to
inflammatory stimuli Three best-known proteins C-reactive protein
(CRP) Fibrinogen Serum amyloid A (SAA) protein
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Systemic Effects of Inflammation Consists of several clinical
and pathologic changes Leukocytosis Common feature of inflammatory
reactions Especially those induced by bacterial infections
Leukocyte count usually climbs to 15,000 or 20,000 cells/ L
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Systemic Effects of Inflammation Consists of several clinical
and pathologic changes Leukocytosis May reach extraordinarily high
levels of 40,000 to 100,000 cells/ L Leukemoid reactions Similar to
the white cell counts observed in leukemia Accelerated release of
cells from the bone marrow Rise in the number of more immature
neutrophils in the blood (shift to the left)
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Systemic Effects of Inflammation Consists of several clinical
and pathologic changes Bacterial infections Increase in the blood
neutrophil count (neutrophilia) Viral infections (infectious mono,
mumps, and German measles) Absolute increase in the number of
lymphocytes (lymphocytosis)
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Systemic Effects of Inflammation Consists of several clinical
and pathologic changes Bronchial asthma, allergy, and parasitic
infestations Increase in the absolute number of eosinophils
(eosinophilia) Infections (typhoid fever and viruses, rickettsiae,
and certain protozoa) Decreased number of circulating white cells
(leukopenia)
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Systemic Effects of Inflammation Consists of several clinical
and pathologic changes Increased pulse and blood pressure Decreased
sweating Redirection of blood flow from cutaneous to deep vascular
beds Minimizes heat loss through the skin Rigors (shivering) Chills
(search for warmth) Anorexia Somnolence
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Consequences of Defective or Excessive Inflammation Defective
inflammation Results in increased susceptibility to infections
Associated with delayed wound healing Provides the necessary
stimulus to get the repair process started Excessive inflammation
Basis of many types of human disease Allergies Disorders in which
the fundamental cause of tissue injury is inflammation