Acute And Chronic Inflammation

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Two main components of inflammation

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Vascular wall response and an inflammatory cell response

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Acute inflammation

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Involves fluid exudation and polymorphonuclear cell emigration

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Chronic inflammation

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Involves lymphocytes and macrophages and inducing blood vessel proliferation and scarring

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Exudate

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n inflammatory extravascular fluid that has a high protein concentration and cellular debris; specific gravity above 1.020

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Transudate

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An extravascular fluid with low protein content and specific gravity below 1.012; an ultrafiltrate of blood plasma resulting from elevated fluid pressures of diminished osmotic forces

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Three major components of acute inflammation that cause clinical presentation

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Alterations in vascular caliber leading to increased blood flow, structural changes in the microvasculature permitting plasma proteins and leukocytes to leave the circulation to produce inflammatory exudates, and leukocyte emigration from blood vessels and accumulation and site of injury

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Vascular changes during inflammation

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Vasodilation (increases hydrostatic pressure) and increased vascular permeability (decreases plasma osmotic pressure)

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Stasis

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When fluid loss causes concentration of red blood cells and increased blood viscosity (when white cells accumulate along the endothelium [margination]) and begin to emigrate through the vessel wall

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Causes of increased vascular permeability

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Formation of endothelial gaps in venules (immediate transient response)(caused by endothelial cell contraction [IL1, TNF, IFN gamma effect cytoskeleton, long lived]), Direct endothelial injury (A,C,V, immediate sustained response), Delayed prolonged leakage (V,C, apoptosis/cytokine effects), Leukocyte-mediated endothelial injury, Increased transcytosis (V, vesiculovacuolar organelle), Leakage from new blood vessels

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Selectins

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Bind through lectin domain

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Immunoglobulin family molecules

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ICAM-1 and VCAM-1; bind integrins on leukocytes

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Mucin-like glycoproteins

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Ligands for leukocyte adhesion molecule CD44; include heparin sulfate

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P-selectin

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Receptor: Sialyl-Lewis X, PSGL-1; Role: Rolling (neutrophils, monocytes, lymphocytes)

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E-selectin

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Receptor: Sialyl-Lewis X; Role: Rolling, adhesion to activated endothelium (neutrophils, monocytes, T-cells)

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ICAM-1

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Receptor: CD11/CD18 (LFA-1, Mac-1) (integrins); Role: Adhesion, arrest, transmigration (all leukocytes)

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VCAM-1

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Receptor: VLA4 (integrin); Role: Adhesion (eosinophils, monocytes, lymphocytes)

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GlyCam-1

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Receptor: L-selectin; Role: lymphocyte homing to high endothelial venules

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CD31 (PECAM)

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Receptor: CD31; Role: leukocyte migration through endothelium

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How chemokines and cytokines affect adhesion and transmigration

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Redistribution of preformed adhesion molecules to the cell surface, Induction of adhesion molecules on endothelium, Increased avidity of binding

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Chemotaxis receptors

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G-protein coupled, cause polymerization of actin and facilitation of cell movement

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Leukocyte activation

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Production of arachidonic acid metabolites, degranulation and secretion of lysosomal enzymes, cytokine secretion, increased adhesion molecule expression and increased integrin avidity

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Receptors involved in leukocyte activation

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G-protein coupled, toll like receptors, receptors for opsonins, receptors for cytokines

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Important recognition proteins for phagocytosis (4)

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Fc fragment, C3b (opsonizers) Macrophage mannose and scavenger receptors

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Killing and degredation of phagocytosed particles (mechanism)

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Activation of NADPH oxidase, converts oxygen to superoxide anion, produces hydrogen peroxide, lysosomal myeloperoxidase converts hydrogen peroxide and chlorine into HOCl

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Oxygen independent methods of microbial killing

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Bactericidal permeability increasing protein, lysozyme, lactoferrin, major basic protein, defensins

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Leukocyte released products that can cause tissue damage

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Lysosomal enzymes (frustrated phagocytosis, premature fusion of lysosomes with forming phagosomes, when lysosomes arae damaged by ingested material), oxygen-derived active metabolites, products of arachidonic acid metabolism

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Leukocyte adhesion deficiency type I

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Defective synthesis of B2 integrins (LFA-1 and Mac-1)

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Leukocyte adhesion deficiency type II

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Defect in fucose metabolism causing loss of sialyl Lewis X

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Genetic defects in phagolysosome formation

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Chediak-Higashi syndrome

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Genetic defects in microbicidal activity (genes encoding NADPH)

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Chronic granulomatous disease

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Acquired deficiencies of neutrophils

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Neutropenia

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General principals surrounding the chemical mediators of inflammation

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Mediators originate either from plasma of from cells, plasma forms must be activated, cell forms are sequestered in intracellular granules or are synthesized de novo, production of active mediators is triggered by microbial products or by host proteins, such as the proteins of the complement, kinin, and coagulation systems, that are themselves activated by microbes and damaged tissues; mediators bind to speciic receptors on target cells, one mediator can stiumulate the release of other mediators by target cells themselves, once activated and released from the cell most of these mediators are short-lived

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Histamine source (3)

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Mast cells (main), platelets, basophils

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Histamine release from mast cell granules caused by? (6)

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Physical injury, immune reactions, anaphylatoxins (complement fragments), histamine-releasing proteins derived from leukocytes, neuropeptides, cytokines

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Serotonin source (2)

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Platelets and enterochromaffin cells

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Causes of serotonin release (2)

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Platelet aggergation, PAF

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Histamine and serotonin effects

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Vasodilation and increased vascular permeability

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Two general categories of the biologic function of complement

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MAC induced cell lysis, and complement fragment induced changes in vascular permeability, chemotaxis, and opsonization

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C3a, C5a, C4a (2): Vascular phenomena

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Vascular phenomena: Stimulate histamine release (anaphylatoxins), C5a activated lipoxygenase pathway of arachidonic acid

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Complement mediated leukocyte adhesion, chemotaxis, and activation

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C5a

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Complement mediated phagocytosis

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C3b and iC3b

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C3 and C5 activation

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Can be by several proteolytic enzymes present within the inflammatory exudate

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Complement regulating factors

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Decay accelerating factor (cell-associated) and C1 inhibitor (circulating)

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Paroxysmal nocturnal hemoglobinuria

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Caused by defects in DAF; characterized by recurrent complement-mediated red cell lysis and anemia

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Hereditary angioneurotic edema

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Caused by C1 inhibitor deficiency; characterized by episodic, potentially life-threatening edema

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Purpose of the kinin system

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To produce vasoactive peptides (bradykinin) from kininogens by the action of proteases called kallikreins

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Bradykinin functions

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Increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels and pain when injected into the skin

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Inactivation of bradykinin

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Kininase, inactivation during passage of plasma thought the lung by angiotensin-converting enzyme

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Kinin cascade

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Factor XII to factor XIIa by surface activation;
Prekallikrein to kallikrein by factor XIIa;
High-mol-weight kininogen to bradykinin by kallikrein

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What acts as a cofactor in the activation of Hageman factor?

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High mol weight kininogen

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What is a potent activator of Hageman factor?

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Kallikrein; allows for autocatalytic amplification of the initial stimulus

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What has chemotactic activity and can also directly convert C5 to C5a?

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Kallikrein

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Clotting system: intrinsic pathway

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Activated by Hageman factor, leads to activation of thrombin, cleavage of fibrinogen, and generation of the fibrin clot

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Fibrinopeptides

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Formed during intrinsic pathway; induces vascular permeability and are chemotactic for leukocytes

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Thrombin inflammatory properties

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Increased leukocyte adhesion to endothelium via binding to specific protease-activated receptors (platelets, endothelial, and smooth muscle cells)

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Activation of Hageman factor

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When it encounters collagen or basement membrane or activated platelets; conformational change that exposes an active serine center

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The main link between coagulation system and inflammation

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Thrombin

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Fibrinolytic system

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Activated by factor XIIa, produces plasmin to degrade fibrin

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PAR-1 induction of inflammation

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Mobilization of P-selectin, production of chemokines, expression of endothelial adhesion molecules; induction of cyclooxygenase-2 and production of prostaglandins; production of PAF and nitric oxide; and changes in endothelial shapes

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Plasmin functions

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Degrades fibrin; cleaves C3, fragments then form fibrin split products that increase vascular permeability and activating Hageman factor

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Systems initiated by Hageman factor

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Kinin system, clotting system, fibrionlytic system. complement system

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Eicosnoids

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Lipid short range signaling molecules from cell membrane derived arachidonic acid, generated by cells responding to activating stimuli

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Major enzyme classes that synthesize eicosanoids

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Cyclooxygenases (prostaglandins, thromboxanes) and lipoxygenases (leukotrienes and lipoxins)

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Prostaglandin I2

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Vasodilation

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Prostaglandin E2

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Vasodilation, sensitivity to painful stimuli, can mediate fever

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Thromboxane A2

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Vasoconstriction

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Leukotrienes C4, D4, E4

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Increase vascular permeability, cause vasodilation

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Leukotrienes B4

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Powerful chemotactic agent

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Lipoxins

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Endogenous negative regulators of leukotriene action

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Platelet activating factor:
Produced by?
Causes?

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Phospholipid derived mediator produced by mast cells and other leukocytes; Causes platelet aggregation/release, bronchoconstriction, vasodilation, increased vascular permeability, increased leukocyte adhesion, leukocyte chemotaxis

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Cytokines produced by?

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Lymphocytes and macrophages

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IL-1 and TNF secretion

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From macrophages, stimulated by endotoxin, immune complexes, toxins, physical injury and a variety of inflammatory products

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IL-1 and TNF acute phase reactions

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Fever, increased sleep, decreased appetite, increased acute phase proteins, hemodynamic effects, neutrophilia

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IL-1 and TNF endothelial activation effects

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Increased leukocyte adherence, PGI synthesis, procoagulant activity, and IL-1, IL-8, IL-6, and PDGF; Decreased anticoagulant activity

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IL-1 and TNF fibroblast effects

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Increased proliferation, collagen synthesis, collagenase, protease, PGE synthesis

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IL-1/TNF leukocyte effects

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Increased cytokine secretion, priming

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CXC chemokines

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IL8; recruitment of neutrophils

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CC chemokines

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Recruitment of monocytes, eosinophils, basophils, and lymphocytes; eotaxin, monocyte chemoattractant protein, macrophage inflammatory protein-1 alpha, RANTES

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Cx3C chemokines

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Fractalkine (in two forms); Cell surface form: firm lymphocyte and monocyte adhesion; Soluble form: chemoattractant for lymphocytes and monocytes

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C chemokines

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Specific for lymphocytes

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NO functions

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Vasodilation, inhibit platelet aggregation and adhesion, kill certain microbes and tumor cells

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NO synthesis

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From arginine, molecular oxygen, NADPH and other cofactors by nitric oxide synthase

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Antimicrobial activity of NO (4)

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Reactive nitrogen intermediates, formation of antimicrobial metabolites by interaction between NO and reactive oxygen species, production increased during host response to infections, genetic inactivation of iNOS enhances microbial replication

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Specific (secondary) granules

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Lysosomal granules in neutrophils that contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, and histaminase

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Azurophil (primary) granules

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Lysosomal granules in neutrophils that contain myeloperoxidase, bactericidal factors, acid hydrolases, and a variety of neutral proteases

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Antiproteases

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Alpha1-antitrypsin; inhibit lysosomal enzymes to keep the inflammatory response in check

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Substance P

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Neuropeptide that mediates vascular permeability, transmits pain signals, regulates blood pressure, and stimulates immune and endocrine cell secretion

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Hypoxia-induced factor 1 alpha

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Produced by cells deprived of oxygen; can induce the inflammatory response on its own

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Mediators of vasodilation (3)

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Prostaglandins, NO, histamine

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Mediators of increased vascular permeablity

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Vasoactive amines, C3a and C5a, bradykinin, leukotrienes C4, D4, E4, PAF, substance P

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Mediators of chemotaxis, leukocyte recruiment and activation

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Leukotriene B4, chemokines, IL-1, TNF, bacterial products

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Mediators of fever

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IL-1, TNF, prostaglandins

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Mediators of pain (2)

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Prostaglandins, bradykinin

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Mediators of tissue damage

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Neutrophil and macrophage lysosomal enzymes, oxygen metabolites, NO

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Serous inflammation

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Marked by an outpouring of a thin fluid that is either derived from the plasma or the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities (effusion)

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Fibrinous inflammation

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Great vascular permeability that results in an exudate rich in fibrinogen. When vascular leaks are large enough or a procoagulant is present

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Suppurative/purulent inflammation

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Characterized by the production of large amounts of pus or purulent exudate consisting of neutrophils, necrotic cells, and edema fluid

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Pyogenic bacteria

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Bacteria that produce a localized suppuration

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Ulcer

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A local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing of inflammatory necrotic tissue

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What chronic inflammation is typified by

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Infiltration with mononuclear inflammatory cells, tissue destruction, attempts at healing

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Cell types involved in chronic inflammation (4)

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Monocytes, lymphocytes, eosinophils, mast cells

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Major basic protein

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A cationic molecule contained in granules in eosinophils. It is toxic to parasites but also lyses mammalian epithelium

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Granulomatous inflammation

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A distinctive pattern of chronic inflammatory reaction characterized by focal accumulation of activated macrophages, which often develop an epithelial like appearance

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Granuloma

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A focus of chronic inflammation consisting of a microscopic aggregation of macrophages that are transformed into epithelium like cells surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells

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Giant cells

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Fused epithelioid cells in the periphery of in the center of granulomas

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Foreign body granulomas

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Incited by relatively inert foreign bodies; caused by fibers that are large enough to preclude phagocytosis and do not incite any specific inflammatory or immune response

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Immune granulomas

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Caused by insoluble particles that are capable of inducing a cell-mediated immune response; produces a granuloma when the inciting agent is poorly degradable or particulate

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Reactive/inflammatory lymphadenitis

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The constellation of lymph nodal histologic changes

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Clinical and pathologic changes associated with the acute phase response

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Fever, acute phase proteins, leukocytosis, increased pulse and BP, decreased sweating, rigors, chills, anorexia, somnolence, malaise