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Inflammation

Inflammation. Dr. Ahmad Hameed MBBS,DCP, M.Phil. Chemical Mediators and regulators of inflammation. Chemical mediators that are responsible for vascular and cellular events of inflammation.

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Inflammation

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  1. Inflammation Dr. Ahmad Hameed MBBS,DCP, M.Phil

  2. Chemical Mediators and regulators of inflammation • Chemical mediators that are responsible for vascular and cellular events of inflammation. • Mediators may be produced locally by cells at inflammation, or may be derived from circulating precursors (typically synthesized by the liver) that are released at the site of inflammation. • Cell-derived mediators are • Sequestered intracellular granules or synthesized de novo • Plasma derived mediators are inactive which undergo proteolytic cleavage to acquire biologic activity. • .

  3. Chemical Mediators and regulators of inflammation • Most mediators act by binding to specific receptors on different target cells. • Diverse action • Direct action • The actions of most mediators are tightly regulated and short lived • Quickly decay • Inactivated by enzymes • Eliminated • inhibited

  4. Cell-Derived Mediators Tissue macrophages, mast cells, and endothelial cells, leukocytes Vasoactive Amines HISTAMINE • Richest source • Mast cells ( C.T , B.V) • Basophils • Platelets Release in response to • Physical injury (trauma, cold, heat) • Immune reactions (Antibody to mast cells) • Anaphylatoxins (C3a & C5a)

  5. Histamine Releasing protein (H.R.P) from leucocytes • Neuropeptides (Substance P ) • Cytokines ( IL-1, IL-8) Action • Immediate transient response (main) • Dilatation of arterioles • Increase permeability of venules • Contricts large arteries • Acts on microcirculation / bind to H1 receptors on endothelial cells

  6. SEROTONIN • 5HT • Similar action • Present in platelets, enterochromaffin cells & neurons • Neurotrasmitter and regulate intestinal motility • When platelet aggregation occurs  release serotonin • Mast cells PAF  platelet aggregation

  7. Archidonic Acid Metabolites: Prostaglandins, Leukotrienes and Lipoxins Microbial Products + Mediators of Inflammation ↓ Arachidonic Acid Prostaglandins Leukotrienes

  8. AA Metabolites • Cyclooxygenase pathway • PGs are Produced by mast cells, macrophages, endothelium and others • PGE2,PGD2,PGF2α • Vasodilation • Potentiates Edema formation • Involved in pathogenesis of pain and fever • PGI2 • Produced by prostacyclinsynthase in endothelial cell • Vasodilation, Inhibits Platelet aggregation • TXA2 • Produced by Thromboxane synthase in platelets • Vasoconstriction & stimulates platelets aggregation, unstable and converts to TXB2

  9. Production of arachidonic acid metabolites and their roles in inflammation.

  10. Lipoxygenase Pathway • LTs are secreted mainly by leukocytes and chemoattractants for leukocytes. • LTA4 • LTB4 • Produced by neutrophils & some macrophages • Chemotactic agent for neutrophils • LTC4 LTD4 & LTE4 • Produced by mast cells • Vasocontriction + bronchospasm + Intravascular Permeability

  11. Anti-inflammatory Drugs that Block Prostagladin Production • NSAID • Inhibit cyclooxygenase • Prevent biosynthesis of all PG • Treat pain and fever • Cyclooxygenase inhibitor • Two isoforms - COX-1/COX-2 • COX-1 • Expressed on most tissues produced in response to inflammation stimulate prostaglandins • COX-2 • Absent most tissues • Developed that they will not affect protective function of prostaglandins • Increased risk of cerebrovascular and cardiovascular events

  12. Lipoxygenase Pathway • Lipoxins (Anti inflammatory mediators ) • Endogenous antagonists of Leukotrienesie inhibit neutrophilchemotaxis and adhesion to endothelium • Platelet adherent to neutrophils from LXA4 and LXB4

  13. Cortisol • Reduces vascular permeability and edema • Decreases prostglandin production by preventing release of AA by inhibiting phospholipase A2

  14. Platelet-Activating Factor • It is generated from a lipid complex stored in cell membranes; Produced by WBCs & endothelial cells • induces platelet aggregation; • Causes Vasoconstriction, Bronchoconstriction • It activates neutrophils and is a potent eosinophilchemoattractant; • It contributes to extravascularization of plasma proteins and so, to edema.

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