DrVShanthi Associate professor Pathology Sri Venkateswara Institute of Medical Sciences Tirupathi CHEMICAL MEDIATORS Inflammatory mediators are the substances that initiate and regulate inflammatory reactions ID: 1000586
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1. CHEMICAL MEDIATORS OF INFLAMMATIONDr.V.ShanthiAssociate professor, PathologySri Venkateswara Institute of Medical Sciences, Tirupathi
2. CHEMICAL MEDIATORSInflammatory mediators are the substances that initiate and regulate inflammatory reactionsMediators originate from either – Plasma - These are present in precursor forms that must be activated by series of proteolytic cleavage to acquire biologic properties e.g. complement proteins & kinins Cells – present in intracellular granules that need to be secreted (e.g. Histamine in mast cells) or synthesized denovo in response to stimulus (e.g. Prostaglandins, cytokines)
3. CHEMICAL MEDIATORS
4. CHEMICAL MEDIATORS
5. CHEMICAL MEDIATORSMediators perform activity by –Mostly by binding to receptors on target cellsDirect enzymatic activity e.g. Lysosomal proteasesMediate oxidative damage e.g. reactive oxygen species & nitrogen intermediatesMediators can act on – One or few target cellsCan have diverse targetsHave different effect on different cell types
6. Once activated & released from the cell the mediators are short lived. They either –Quickly decay e.g. Arachidonic acid metabolitesInactivated by enzymes e.g. kininase inactivates BradykininScavenged e.g. antioxidants scavenge toxic oxygen metabolitesInhibited e.g. complement regulatory proteins breakup & degrade activated complement componentsCHEMICAL MEDIATORS
7. First mediators to be released during inflammation are - Histamine SerotoninCHEMICAL MEDIATORSVasoactive amines
8. HISTAMINERichest source – mast cells - also in platelets & BasophilsStimuli for degranulation of Mast cells –Physical injury such as trauma , cold or heatImmune reactions involving binding of antibodies to Mast cellsFragments of complement called Anaphylotoxins (C3a & C5a )Neuropeptides (substance P )Cytokines (IL – 1 & IL – 8 ) CHEMICAL MEDIATORS
9. HISTAMINEAction of HistamineDilation of arterioles ( but constriction of large arterioles )Increased permeability of veinulesPrinciple mediator of immediate transient phase of increased vascular permeabilityActs on microcirculation mainly via binding to H1 receptor on endothelial cellsCHEMICAL MEDIATORS
10. SEROTONINAction similar to that HistamineSource – platelets & Enterochromaffin cells Release from platelets occurs when platelets aggregate after contact with –CollagenThrombinADPAg- Ab complexesCHEMICAL MEDIATORS
11. Plasma proteins that mediate inflammatory response belong to 3 interrelated systemsComplement systemKinin systemClotting systems CHEMICAL MEDIATORSPLASMA PROTEINS
12. COMPLEMENT SYSTEMComplement system consists of 20 component proteins that are found in greatest concentration in plasmaComplement components causes – Increasing vascular permeabilityChemotaxisOpsonisationCHEMICAL MEDIATORS
13. Complement systemThe early steps in complement activation consists of 3 pathways i.e. – Classical pathwayAlternate pathwayLectin pathwayCHEMICAL MEDIATORS
14. COMPLEMENT SYSTEMActivation of complement cascade consists of 2 steps i.e. early step & late stepEarly steps consists of 3 different pathways & lead to proteolytic cleavage of C3Late steps – all 3 pathways converge & major breakdown products of C3, C3b activate a series of other complement componentsCHEMICAL MEDIATORS
15. CHEMICAL MEDIATORS - PLASMA PROTEINSclassical pathwayC1Activated C1C4+C2C4b2bClassical pathwayC3 convertaseAg-Ab complexC3C3aC3bC4b2b3bClassical pathway C5 convertaseRecruitment and activation of leukocytes
16. CHEMICAL MEDIATORS- PLASMA PROTEINSAlternate pathwayC3C3bC3b +microbial polysaccharideFactor BFactor DC3bBbAlternate pathway C3 convetaseC3C3aC3bC3bBb3bAlternate pathway C5 convertaseRecruitment and activation of leukocytes
17. CHEMICAL MEDIATORS- PLASMA PROTEINSLECTIN PATHWAYC1Activated C1C4+C2C4b2bC3C3bC3aC4b2b3bRecruitment and activation of leukocytesC3 convertaseC5 convertase
18. CHEMICAL MEDIATORS- PLASMA PROTEINSLATE PATHWAYC4b2b3bC3bBb3bClassical & Lectin pathway C5 convertaseAlternate pathway C5 convertaseC5C5aC5bC5 - 9C6C7C8C9Membrane attack complexRecruitment and activation of leukocytesLysis of microbes
19. ACTIVATION AND FUNCTIONS OF COMPLEMENT SYSTEM
20. CHEMICAL MEDIATORS OF INFLAMMATIONPLASMA PROTEINSThe biologic function of complement systemCell lysis by MAC Vascular phenomenon – increased vascular permeability & vasodilatationLeukocyte adhesion, chemotaxis & activationPhagocytosis
21. CHEMICAL MEDIATORS OF INFLAMMATIONPLASMA PROTEINSRegulation of complement activationRegulation of C3 & C5 convertase by enhancing dissociation of convertase complex e.g. Decay accelerating factorFactor H – causes cleavage of C3b and turnover of C3 convertaseBinding of active complement components by specific proteins in plasmaC1 inhibitor interferes with enzymatic activity of C1Proteins that inhibit MAC formation e.g. CD59 inhibit excessive complement activation
22. CHEMICAL MEDIATORS OF INFLAMMATIONPLASMA PROTEINSDisorders of complement systemDeficiency of complement components lead to increased susceptibility to infectionsDeficiency of C4 & C2 – autoimmune diseases e.g. SLEGenetic defeciency of complementary regulatory protein – significant disease – e.g. Paroxysmal Nocturnal Hemoglobinuria Deficiency of C1 inhibitor – Hereditary angioneurotic edema
23. CHEMICAL MEDIATORSkinin systemFACTOR XIICollagen, Basement membrane, and activated plateletsFACTOR XIIaKinin cascadeClotting cascadePrekallikrein Kallikrein Fibrinolytic systemHigh molecular weight kininogenBradykinin Increased vascular permeabilityCauses smooth muscle contractionDilation of blood vesselsPain XIIaHMWK
24. XIIaFactor XIFactor XIaFactor XFactor XaProthrombin Thrombin Protease activated receptorsACUTE INFLAMMATION CHEMICAL MEDIATORSClotting systemFactor IIFactor IIa
25. CHEMICAL MEDIATORS OF INFLAMMATIONClotting systemProtease activated receptorsThese are 7- Transmembrane G – protein receptors present on platelets, endothelial cells, smooth muscle cells, etc.Engagement of PAR by proteases particularly Thrombin triggers several responses like- Mobilization of P- selectinProduction of chemokinesExpression of endothelial adhesion moleculeProduction of Prostaglandins, PAF, & NOChanges in endothelial shape
26. Kallikrein PlasminogenPlasminC3C3aFibrin Fibrinogen Fibrin split products Fibrinopeptides Thrombin CHEMICAL MEDIATORSClotting systemComplement cascade
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