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Mediators of inflammation

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Mediators of inflammation

  1. 1. Mediators of inflammation 2 Definition: Chemical mediators that are responsible for vascular and cellular events. • It may either of two types, – Cell Derived - produced locally by cells at the site of inflammation – Plasma derived – mainly from liver • Some mediators are derived from Necrotic cells
  2. 2. Classification 3 Cell derived mediators Plasma derived mediators
  3. 3. 4
  4. 4. 1. Cell derived mediators 5 a) vasoactive amines(serotonin,histamine) b) Arachidonic acid metabolites  cycloxygenase pathway  lipoxygenase pathway c) Lysosomal components d) Platelet activating factor e)Cytokines (IL-1,TNF-α,TNF-β,IF-γ,Chemokines) f) Nitric oxide andoxygen metabolites
  5. 5. a) Vasoactive amines Histamine :- Histamine is an organic nitrogenous compound as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Mast cells are richest source of histamine, basophiles and platelets. Released by the stimuli of various agents like Heat, Cold, Irradiation, Irritant chemicals,Anaphilatoxins, Interleukins,.. etc. Actions ; Vasodilation Vascularpermeability Itching and pain 6
  6. 6. Serotonin/5-hydroxy tryptamine :- The scientific name for serotonin is 5-hydroxytryptamine, or 5-HT. It is mainly found in the chromafin cells of GIT, Spleen,Nervous tissue, Mast cells,Platelets. brain, bowels, and blood. Actions ; Similar to Histamine, but lesspotent Vasodilation Vascularpermeability 7
  7. 7. b) Arachidonic acid Metabolites Arachidonic acid is a polyunsaturated fatty acid • produced by endothelial cells, leukocytes and platelets • act locally on smooth muscle, endothelium and platelets • origin: Arachidonic acid derived from dietary sources or by conversion from the linoleic acid. And released by activated phospholipases (in injury) • two important pathways:  cyclooxygenase (COX)  lipoxygenase
  8. 8. • AA Metabolites – Cyclooxygenase pathway • PGD2,PGE2,PGF2α (prostaglandin) – V.D – Potentiates Edema formation • PGI2(prostacyclin) – Produced by prostacyclin synthase in endothelial cell – V.D, Inhibits Platelet aggregation • TxA2( throboxane A2) – Produced by Thromboxane synthase in pllatelets – stimulates platelets aggregation
  9. 9. Cyclooxygenase Pathway
  10. 10. – Lipoxygenase Pathway: present in neutrophils • LTB4 – Produced by neutrophils & some macrophages – Chemotactic agent for neutrophils • LTC4,LTD4 & LTE4 – Produced by mast cells – V.C bronchospasm • Lipoxins – Endogenous antagonists of Leukotrienes • PAF Platelet-activating factor, or AGEPC (acetyl-glyceryl-ether- phosphorylcholine), is a potent phospholipid activator and mediator of many leukocyte functions,platelet aggregation • Produced by WBCs & endothelial cells • Causes V.C, Bronchoconstriction
  11. 11. Lipoxygenase Pathway HPETE, hydroperoxyeicosatetraenoic acid. HETE, hydroxyeicosatetraenoic acid;
  12. 12. Major effects of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in inflammation
  13. 13. c) Lysosomal components 1 4 Source :- Neutrophiles andmonocytes Potent mediators Realease of acid proteases, collagenase,elastase, plasminogen activator Lysosomes contain a wide variety of enzymes such as nucleic acids, proteins, and polysaccharides.
  14. 14. d) Platelet activating factor  Phospholipid derived mediator  Released from :- Platelets, basophil, mastcells, neutrophils macrophages, endothelialcells  Actions :-  Vascularpermeability  Vasoconstriction  Vasodilatation 15 Also known as PAF, or AGEPC (acetyl-glyceryl-ether- phosphorylcholine), is a potent phospholipid activator and mediator of many leukocyte functions, platelet aggregation and degranulation, inflammation,
  15. 15. e) Cytokines 16 “Cytokines are proteins produced by many cell types (activated lymphocytes, macrophages, and dendritic cells).” • Cytokines – Some mediate communication between WBCs(Interleukins) – Some play role in inflammation(TNF, IL-1, Chemokines, IFN-γ ,IL-12) – mediate and regulate immune and inflammatory reactions
  16. 16. Actions :-  Adhesion of leucocytes toendothelium  S ynthesis of Prostacyclin, which is avasodilatorand anti aggregator of platelets  Synthesis of thrombogenic effecton endothelial surface 17
  17. 17. f) Nitric oxide and oxygen metabolites 18 Functions of nitric oxide (NO) in blood vessels and macrophages, produced by two NO synthase enzymes. NO causes vasodilation, and NO free radicals are toxic to microbial and mammalian cells. NOS: nitric oxide synthase.
  18. 18. 2.Plasma derived mediators 19 a) The kininsystem : b) The clottingsystem : c) The fibrinolyticsystem : d) The complementsystem :
  19. 19. 2: Plasma Protein derived mediators Pa a)Kinin System: The kinin– kallikrein system or simply kinin system is a poorly hormonal system . It consists of blood proteins that play a role in inflammation, blood pressure control, coagulation and pain. – Ultimately leads to formation of bradykinin – Bradykinin causes – Arteriolar dilation, increases vascular permeability & broncho constriction
  20. 20. a) The kinin system factorXII contact factorXIIa prekallikrein activator Plasmaprekallikrein kallikrein kininogen Bradykinin blood vessels to dilate (enlarge) 21
  21. 21. • Clotting System: Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot – 12a → 11a → 10a → 2a (Thrombin) – Thrombin converts fibrinogen into fibrin & generates fibrinopeptides – Fibrinopeptides → Increased Vascular permeability & chemotactic for WBCs
  22. 22. b) Clotting system factorXII contact factorXIIa XI XIa +VIIa +PF3 X Xa +Va+PF3 prothrombin thrombin fibrino fibrinogen fibrin Peptides plasmin 23
  23. 23. Fibrinolytic System: to remove the clot after the vasculature is repaired, as well as to degrade clots that form in the bloodstream. – Ultimately leads to formation of plasmin – Plasmin • converts C3 to C3a • Converts factor-12 to factor-12a • Breaks down fibrin to fibrin degradation products which further increases the vascular permeability
  24. 24. C) Fibrinolytic system 25
  25. 25. – Mainly leads to the formation of C3a & C5a – Vascular effects( C3a & C5a) – Leukocyte activation, adhesion, chemotaxis(C5a) – Phagocytosis(C3b,iC3b) Complement System: The complement system is a collection of soluble proteins The complement system is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to microbes and damaged cells from an organism, promotes inflammation, and attacks the pathogen's plasma membrane  Membraneattackcomplexcausepores in cell of invading microbes.
  26. 26. Three pathways: • Classical pathway (antibodies) • Alternate pathway (microbe LPS) • Lectin pathway (sugar on microbes)
  27. 27. Interrelationships between the four plasma mediator systems triggered by activation of factor XII (Hageman factor). Note that thrombin induces inflammation by binding to protease-activated receptors (principally PAR-1) on platelets, endothelium, smooth muscle cells, and other cells.