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INFLAMMATORY MEDIATORS

Submitted by : Rafa Zubair NVI M.Pharm

PharmacologySubject: Biochemical and molecular pharmacology

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Mediators of inflammation

Definition: Any messenger that acts on blood vessels, inflammatory cells, or other cells to contribute to an inflammatory response.

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Classification

Cell derived mediators

Plasma derived mediators

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1. Cell derived mediatorsa) vasoactive amines (serotonin,histamine)b) arachidonic acid metabolites

cycloxygenase pathway lipoxygenase pathway

c) Lysosomal components d) Platelet activating factore) Cytokines (IL-1,TNF-α,TNF-β,IF-γ,Chemokines)f) Nitric oxide and oxygen metabolites

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a) Vasoactive amines Histamine :-Stored in granuls of mast cells, basophiles and

platelets.Released by the stimuli of various agents like

Heat, Cold, Irradiation, Irritant chemicals, Anaphilatoxins, Interleukins,.. etc.

Actions ; Vasodilation Vascular permeability Itching and pain

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Serotonin/5-hydroxy tryptamine :-Present in chromafin cells of GIT, Spleen,

Nervous tissue, Mast cells, Platelets.Actions ; Similar to Histamine, but less

potent Vasodilation Vascular permeability

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b) Arachidonic acid MetabolitesLipoxygenase pathway Cyclo-

oxygenase pathway

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c) Lysosomal comonentsSource :- Neutrophiles and monocytes

Potent mediatorsDegredation of bacterial and extracellular

componentsChemotaxisRealease of acid proteases, collagenase,

elastase, plasminogen activator

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d) Platelet activating factorPhospholipid derived mediatorReleased from :- Platelets, basophil, mast cells,

neutrophils macrophages, endothelial cellsActions :- Vascular permeability Vasoconstriction Vasodilatation Bronchoconstriction Adhesion of leukocytes to endothelium Chemotaxis, degranulation

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e) Cytokines“Cytokines are a diverse group of small protein

molecules with potent biological activity whose main function is in the regulation of immune responses.”

Main Cytokines are :- InterleukinsInterferonsTumor necrosis factor ChemokinesTransforming growth factor-betaAdipokines- leptin & adiponectin

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Actions :- Adhesion of leucocytes to endothelium Synthesis of Prostacyclin, which is a

vasodilator and anti aggregator of platelets Synthesis of PAF and thrombogenic effect on

endothelial surface

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f) Nitric oxide and oxygen metabolitesEndothelium derived relaxing factorMacrophages, endothelial cells, neuronsActions :- Vasodilation Anti-platelet activating agent Microbicidal actionH2O2 , Superoxide, Toxic NO products produced

by activated neutrophiles and microphagesActions :- Endothelial cell damage, tissue damage and

vascular permeability

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2.Plasma derived mediators

a) The kinin systemb) The clotting systemc) The fibrinolytic systemd) The complement system

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4 interlinked systemsHageman factor(factor XII)End product of clotting ,fibrinolytic ,kinin

system will activate complement system.

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a) The kinin system factor XII contact factor XIIa

prekallikrein activator

Plasma prekallikrein kallikrein

kininogen bradykinin

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Actions :-

Smooth muscle contractionVasodilation vascular permeabilitypain

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b) Clotting system factor XII contact factor XIIa

XI XIa +VIIa +PF3

X Xa +Va +PF3

prothrombin thrombin

fibrino fibrinogen fibrinPeptides plasmin

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Actions :- Increase vascular permeabilityChemotaxis for leucocytesAnticoagulant activity

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C) Fibrinolytic system

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Actions :- Activation of factor XII to form prekallikrein

activator that stimulates kinin system to generate bradykinin

Splits off complement c3 to form c3a,which is permeability factor

Degrades fibrin to split products, they increase vascular permeability

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D) Complement systemProduct of complement system is

anaphylatoxins c3a and c5a.Potency is c3a>c5a>c4aActions:- release histamine from mast cells

and basophilsC5a is chemotactic for leucocytes.Membrane attack complex cause pores in cell

of invading microbes.