MEDIATORS MEDIATORS OF OF

INFLAMMATIONINFLAMMATION

INTRODUCTIONINTRODUCTION Any messenger that acts on blood vessels , Any messenger that acts on blood vessels ,

inflammatory cells or other cells to inflammatory cells or other cells to contribute to an inflammatory response.contribute to an inflammatory response.

Active mediators are produced in response Active mediators are produced in response to various stimuli such as microbial to various stimuli such as microbial products , coagulation & complement products , coagulation & complement systems.systems.

One mediator can stimulate the release of One mediator can stimulate the release of other mediators.other mediators.

Mediators vary in range of cellular targets.Mediators vary in range of cellular targets. Once activated & released from cell, most Once activated & released from cell, most

mediators are short lived.mediators are short lived.

Mediators are generated either from cell or from plasma Mediators are generated either from cell or from plasma proteins.proteins. Cell derived mediators are sequestered in intracellular Cell derived mediators are sequestered in intracellular

granules & rapidly secreted by exocytosis or granules & rapidly secreted by exocytosis or synthesized de novo in response to stimulus.synthesized de novo in response to stimulus.

Plasma derived mediators produced mainly in liver & Plasma derived mediators produced mainly in liver & present in circulation as inactive precursors which are present in circulation as inactive precursors which are activated by series of proteolytic cleavages.activated by series of proteolytic cleavages.

CELL DERIVED CELL DERIVED MEDIATORSMEDIATORS HISTAMINE HISTAMINE

MAST CELLSMAST CELLS Richest source of histamineRichest source of histamine Located in connective tissue adjacent Located in connective tissue adjacent

to blood vesselsto blood vessels Degranulation through receptors for Degranulation through receptors for

IgE- , IgG , Anaphylatoxins C5a , IgE- , IgG , Anaphylatoxins C5a , physical injury & cytokines. physical injury & cytokines.

Rapidly released mediators of Rapidly released mediators of inflammationinflammation

Histamine causes dialatation of arterioles Histamine causes dialatation of arterioles & increases permeability of venules.& increases permeability of venules.

Effects are mediated via binding to H1 Effects are mediated via binding to H1 receptors on EC.receptors on EC.

ARACHIDONIC ACID ARACHIDONIC ACID METABOLITESMETABOLITES

20 – carbon polyunsaturated fatty acids.20 – carbon polyunsaturated fatty acids. Derived from linoleic acid.Derived from linoleic acid. Esterified in membrane phospholipid ; Esterified in membrane phospholipid ;

released through action of cellular released through action of cellular phospholipase A2.phospholipase A2.

2 major pathways :2 major pathways : COX pathway : has constitutively expressed COX pathway : has constitutively expressed

COX-1 and inducible enzyme COX-2 ; Stimulate COX-1 and inducible enzyme COX-2 ; Stimulate the release of Prostaglandins : produced by the release of Prostaglandins : produced by mast cells , macrophages , endothelial cells etc.mast cells , macrophages , endothelial cells etc.

Lipoxygenase pathway : stimulate release of Lipoxygenase pathway : stimulate release of leukotrienes by leukocytes.leukotrienes by leukocytes.

PROSTAGLANDINSPROSTAGLANDINS PGI2 ( prostacyclins) PGI2 ( prostacyclins)

VasodialatorVasodialator Inhibitor of platelet aggregationInhibitor of platelet aggregation Markedly potentiates permeability increasing & Markedly potentiates permeability increasing &

chemotactic effects.chemotactic effects. PGD2 & PGE2 PGD2 & PGE2

Major prostaglandins produced by mast cells.Major prostaglandins produced by mast cells. Causes vasodialatation & increases permeability of Causes vasodialatation & increases permeability of

post capillary venules ; thus potentiating edema post capillary venules ; thus potentiating edema formation.formation.

PGD2 acts as chemoattractant for neutrophils.PGD2 acts as chemoattractant for neutrophils. PGE2 is hyperalgesic & produces hypersensitivity PGE2 is hyperalgesic & produces hypersensitivity

to painful stimulito painful stimuli PGF2PGF2αα : stimulates contraction of uterine & bronchial : stimulates contraction of uterine & bronchial

smooth muscles & small arterioles.smooth muscles & small arterioles.

LEUKOTRIENESLEUKOTRIENES LTB4 LTB4

Potent chemotactic agent.Potent chemotactic agent. Activator of neutrophils.Activator of neutrophils. Causes aggregation & adhesion of cells to Causes aggregation & adhesion of cells to

venular endothelium.venular endothelium. Generation of reactive oxygen species.Generation of reactive oxygen species. Release of lysosomal enzymes.Release of lysosomal enzymes.

LTC4 , LTD4 & LTE4 LTC4 , LTD4 & LTE4 Intense vasoconstrictionIntense vasoconstriction bronchospasmbronchospasm Increased vascular permeabilityIncreased vascular permeability

LIPOXINSLIPOXINS Inhibitors of inflammation.Inhibitors of inflammation. Principle action is to inhibit leukocyte Principle action is to inhibit leukocyte

recruitment & cellular components of recruitment & cellular components of inflammation.inflammation.

Inhibit neutrophil chemotaxis & Inhibit neutrophil chemotaxis & adhesion to endothelium.adhesion to endothelium.

Lipoxins are endogenous negative Lipoxins are endogenous negative regulators of leukotrienes & thus regulators of leukotrienes & thus play a role in mediators of play a role in mediators of inflammation.inflammation.

REACTIVE OXYGEN SPECIESREACTIVE OXYGEN SPECIES Released Released

extracellularly from extracellularly from leukocytes after leukocytes after exposure to microbes , exposure to microbes , chemokines & immune chemokines & immune complexes or following complexes or following a phagocytic challenge.a phagocytic challenge.

NADPH oxidase NADPH oxidase system:system: Superoxide anion , Superoxide anion ,

H2O2 & hydroxyl H2O2 & hydroxyl radical are major radical are major species.species.

Implicated in following responses of Implicated in following responses of inflammationinflammation Endothelial cell damage & increased Endothelial cell damage & increased

vascular permeability.vascular permeability. Injury to other cell types ( Parenchymal Injury to other cell types ( Parenchymal

cells & RBCs )cells & RBCs ) Inactivation of anti-protease such as Inactivation of anti-protease such as αα--

antitrypsin.antitrypsin. Leads to unopposed protease activity with Leads to unopposed protease activity with

increased destruction of extracellular increased destruction of extracellular matrix. matrix.

NITRIC OXIDENITRIC OXIDE Released from endothelial cells to cause Released from endothelial cells to cause

vasodialatation ; Endothelium derived relaxing vasodialatation ; Endothelium derived relaxing factor.factor.

Also produced by macrophages & neurons.Also produced by macrophages & neurons. Sythesized from L-argenine by enzyme nitric Sythesized from L-argenine by enzyme nitric

oxide synthase (NOS)oxide synthase (NOS) eNOS & nNOS constitutively expressed at low levels & eNOS & nNOS constitutively expressed at low levels &

can be activated by an increase in cytoplasmic calcium.can be activated by an increase in cytoplasmic calcium. iNOS induced when macrophages & other cells are iNOS induced when macrophages & other cells are

activated by cytokines.activated by cytokines. Has dual actions in inflammation Has dual actions in inflammation

Promotes vasodialatation.Promotes vasodialatation. Inhibition of cellular components of inflammatory Inhibition of cellular components of inflammatory

responses.responses. Reduces platelet aggregation & adhesion ; Reduces platelet aggregation & adhesion ;

inhibits leukocyte recruitmentinhibits leukocyte recruitment

CYTOKINESCYTOKINES TNF & IL1TNF & IL1

2 major cytokines that mediate inflammation.2 major cytokines that mediate inflammation. Produced mainly by activated macrophages.Produced mainly by activated macrophages. Induce the expression of endothelial adhesion Induce the expression of endothelial adhesion

molecules & synthesis of chemical mediators.molecules & synthesis of chemical mediators. Responsible for production of enzymes associated Responsible for production of enzymes associated

with matrix remodelling.with matrix remodelling. Increase in surface thrombogenicity of Increase in surface thrombogenicity of

endotheliumendothelium Act on thermoregulatory centre in hypothalamus ; Act on thermoregulatory centre in hypothalamus ;

induce the production of PGE & results in fever.induce the production of PGE & results in fever. IL6 acts on liver to increase the production of IL6 acts on liver to increase the production of

complement components & coagulation complement components & coagulation factors.factors.

CHEMOKINESCHEMOKINES Classified into four major groups :Classified into four major groups :

C-X-C chemokines (IL-8)C-X-C chemokines (IL-8) Activation & chemotaxis of neutrophilsActivation & chemotaxis of neutrophils

C-C chemokines (C-C chemokines (ββ chemokines ) chemokines ) Includes monocyte chemoattractant protein (MCP-1) , Includes monocyte chemoattractant protein (MCP-1) ,

eotaxin , macrophage inflammatory protein – 1eotaxin , macrophage inflammatory protein – 1α , α , RANTES.RANTES.

Attract monocytes , eosinophils , basophils & Attract monocytes , eosinophils , basophils & lymphocytes but not neutrophils.lymphocytes but not neutrophils.

C chemokines (C chemokines (γγ chemokines ) chemokines ) Specific for lymphocytes.Specific for lymphocytes.

CX3C chemokinesCX3C chemokines Cell surface bound proteinCell surface bound protein Soluble formSoluble form

PLASMA PROTEIN DERIVED PLASMA PROTEIN DERIVED MEDIATORSMEDIATORS

3 inter-related systems are activated 3 inter-related systems are activated within this categorywithin this category KININ YSTEMKININ YSTEM

Highly vasoactiveHighly vasoactive COMPLEMENT SYSTEM COMPLEMENT SYSTEM

Vasoactive Vasoactive ChemotacticChemotactic

CLOTTING SYSTEM CLOTTING SYSTEM Vasoactive Vasoactive Cleaves C3Cleaves C3

COMPLEMENT SYSTEMCOMPLEMENT SYSTEM Plasma proteins - act against microbial Plasma proteins - act against microbial

agentsagents Products of activated complementProducts of activated complement

Vascular permeabilityVascular permeability ChemotaxisChemotaxis OpsonizationOpsonization LysisLysis

COMPLEMENT SYSTEMCOMPLEMENT SYSTEMFew reminders

Classical pathwayClassical pathway Alternate pathwayAlternate pathway Common pathwayCommon pathway Important inflammatory mediatorsImportant inflammatory mediators

C3a and C5a (anaphylatoxins)C3a and C5a (anaphylatoxins)–Cause release of histamine from mast cellsCause release of histamine from mast cells–Lysosomal enzyme release in inflammatory cellsLysosomal enzyme release in inflammatory cells

C5aC5a–Activates lipoxygenase pathwayActivates lipoxygenase pathway–Chemotactic many inflammatory cellsChemotactic many inflammatory cells–Increases adhesion of leukocytesIncreases adhesion of leukocytes

COMPLEMENT SYSTEMCOMPLEMENT SYSTEM Opsonization : A process in which Opsonization : A process in which

opsonin molecule binds on one side to opsonin molecule binds on one side to particulate matter & binds with particulate matter & binds with receptors on phagocytic molecules on receptors on phagocytic molecules on other side.other side.

C3b & IgG are opsonins facilitating the C3b & IgG are opsonins facilitating the phagocytic process.phagocytic process.

C5b-9 membrane attack complexC5b-9 membrane attack complex Lyses cellsLyses cells Stimulates arachidonic acid metabolismStimulates arachidonic acid metabolism Produces reactive oxygen metabolitesProduces reactive oxygen metabolites

KININ SYSTEMKININ SYSTEM Kinins are vasoactive peptides derived from Kinins are vasoactive peptides derived from

Kininogen by action of KallikreinsKininogen by action of Kallikreins

Activated by Hageman factor (XIIa) Activated by Hageman factor (XIIa)

BRADYKININBRADYKININ Potent vasodilator Potent vasodilator Increased vascular permeabilityIncreased vascular permeability Contraction of smooth muscleContraction of smooth muscle Produce painProduce pain

Kallikrein itself is a potent activator of Kallikrein itself is a potent activator of Hageman factor allowing for autocatalytic Hageman factor allowing for autocatalytic amplification of initial stimulus. amplification of initial stimulus.

COAGULATION SYSTEMCOAGULATION SYSTEMClotting system

Plasma proteins Plasma proteins Can be activated by Hageman factorCan be activated by Hageman factor

Thrombin converts fibrinogen to fibrin Thrombin converts fibrinogen to fibrin Fibrinopeptides are formedFibrinopeptides are formed

–↑↑vascular permeabilityvascular permeability–Chemotactic for leucocytesChemotactic for leucocytes

Plasmin is important in lysing fibrin clots,Plasmin is important in lysing fibrin clots, Activates Hageman factor (XII) ⇨ bradykininActivates Hageman factor (XII) ⇨ bradykinin Cleaves C3 ⇨ C3a Cleaves C3 ⇨ C3a "fibrin-split products" formed from fibrin "fibrin-split products" formed from fibrin

breakdownbreakdown–↑ ↑ vascular permeabilityvascular permeability

HAGEMAN FACTOR HAGEMAN FACTOR Dependent Factors

Factor XII of intrinsic coagulation Factor XII of intrinsic coagulation cascadecascade

Involved in :Involved in : KININ SYSTEM : produces vasoactive KININ SYSTEM : produces vasoactive

kininskinins CLOTTING SYSTEM : induces thrombin CLOTTING SYSTEM : induces thrombin

formationformation FIBRINOLYTIC SYSTEM : produces FIBRINOLYTIC SYSTEM : produces

plasmin & degrades fibrin to produce plasmin & degrades fibrin to produce fibrinopeptides.fibrinopeptides.

COMPLEMENT SYSTEM : To produce COMPLEMENT SYSTEM : To produce anaphylatoxins & other mediatorsanaphylatoxins & other mediators

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