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Inflammation 5
- 1. Inflammation and Repair - 5 Dr.CSBR.Prasad, M.D. v3-CSBRP-May-2012
- 2. Sequence of events in Inflammation Vascular Cellular • Vasodilation • Margination • Increased vascular • Rolling permeability • Adhesion • Diapedesis • Chemotaxis • Phagocytosis • Killing & degradation v3-CSBRP-May-2012
- 3. Events are reflected clinically by Cardinal signs of inflammation • Rubor • Calor • Dolar • Tumor • Loss of function v3-CSBRP-May-2012
- 4. Chemical Mediators of Inflammation v3-CSBRP-May-2012
- 5. Chemical Mediators Def: Any messenger that acts on blood vessels, leucocytes, or other cells to contribute to an inflammatory response v3-CSBRP-May-2012
- 6. Chemical Mediators • Vasodilation – Prostaglandins, Nitric Oxide • Increased Vascular Permeability – Vasoactive amines (histamine, serotonin), C3a and C5a, Bradykinin, Leukotrienes, PAF • Chemotaxic Leukocyte Activation – C5a, LTB4, Chemokines v3-CSBRP-May-2012
- 7. Chemical Mediators • Fever – IL-1, IL-6, TNF, PGE2 • Pain – Prostaglandins, Bradykinin • Tissue Damage – Neutrophil and Macrophage products – Lysosomal enzymes – Oxygen metabolites – NO v3-CSBRP-May-2012
- 8. Chemical Mediators General properties: • They are generated from: Cells Plasma proteins • Mediators are produced in response to various stimuli • One mediator can stimulate the release of other [Guarantees amplification and maintenance of inflammatory response] • Mediators vary in their range of cellular targets • Majority are short-lived [Short t ½ and are harmful] v3-CSBRP-May-2012
- 10. Cell derived mediators Vasoactive Amines: Histamine and Serotonin AA Metabolites: PGs, LTs, and Lipoxins Platelet-Activating Factor (PAF) ROS Nitric Oxide (NO) Cytokines and Chemokines Tumor Necrosis Factor and Interleukin-1 Chemokines Other Cytokines IL6, IL17 Lysosomal Constituents of Leukocytes Neuropeptides v3-CSBRP-May-2012
- 11. Plasma derived mediators PLASMA PROTEASES 3 interrelated systems are active within this category 1. Kinin system Highly vasoactive 2. Complement system Vasoactive Chemotactic 3. Clotting system Vasoactive Cleaves C3 v3-CSBRP-May-2012
- 12. Cell derived mediators Vasoactive Amines: Histamine and Serotonin AA Metabolites: PGs, LTs, and Lipoxins Platelet-Activating Factor (PAF) ROS Nitric Oxide (NO) Cytokines and Chemokines Tumor Necrosis Factor and Interleukin-1 Chemokines Other Cytokines IL6, IL17 Lysosomal Constituents of Leukocytes Neuropeptides v3-CSBRP-May-2012
- 13. Cell derived mediators Vasoactive Amines: Histamine and Serotonin • Increase Vascular Permeability • Histamine and Serotonin Mediators in the immediate active phase of increased permeability – Promotes contraction of smooth muscle – Stimulates to cells to produce eotaxins v3-CSBRP-May-2012
- 14. Cell derived mediators Vasoactive Amines: Histamine and Serotonin • Releasing Stimulators – Direct physical or chemical injury – Binding of IgE- Ag- complexes – Fragments of C3a and C5a – Histamine releasing factors (pmn’s and θ) – Cytokines (IL-1, IL-8) – Neuropeptides v3-CSBRP-May-2012
- 15. ARACHIDONIC ACID METABOLITES • Roles in many biologic and • Via activation of cellular pathologic processes phospholipases – Inflammation – By mechanical, chemical • 20-carbon polyunsaturated and physical stimuli or by other mediators fatty acid – Derived directly from dietary • 2 major pathways sources or by conversion of – Cyclooxygenase pathway essential fatty acid linoleic – Lipoxygenase pathway. acid • Esterified in membrane phospholipids – Must first be released from phospholipids v3-CSBRP-May-2012
- 17. CYCLOOXYGENASE PATHWAY • 2 cyclooxygenase enzymes – COX-1 – COX-2 • 3 important products – Thromboxane A2 – Aggregates platelets and causes vasoconstriction – Prostacyclin (PGI2) – Endothelial cells inhibits platelet aggregation and causes vasodilation – Prostaglandins PGE2, PGF2 and PGD2 – Variety of actions on vascular tone and permeability v3-CSBRP-May-2012
- 18. LIPOXYGENASE PATHWAY Leukotrienes - LT • LT B4 is a potent chemotactic agent • Leukotrienes C4, D4, E4 – Potent vasoconstrictors – Potent mediators of increased vascular permeability on venules only – Up to 1000 times as potent as histamine in producing increased vascular permeability v3-CSBRP-May-2012
- 19. NOTE: Some anti-inflammatory drugs interfere with arachidonic acid metabolism – Corticosteroids interfere with phospholipase – Aspirin interferes with cyclooxygenase v3-CSBRP-May-2012
- 20. PLATELET ACTIVATING FACTOR - PAF • Aggregate platelets and cause release • Bronchoconstriction and Vasoconstriction • ↑ vascular permeability • ↑ leukocyte adhesion • Leukocyte chemotaxis v3-CSBRP-May-2012
- 21. CYTOKINES • Transmitters for cell-to-cell chatting – Modulate cell function • Primarily from activated macrophages and lymphocytes • IL-1, IL-8, TNF v3-CSBRP-May-2012
- 22. IL-I and TNF “Master Cytokines” • Origin – Monocytes – Macrophages • Similar in action • Endothelium • Acute phase proteins • Fibroblasts v3-CSBRP-May-2012
- 24. Other Cytokines • IL-5 – Eosinophils • IL-6 – B and T cells • IL-8 – Neutrophils – Lesser degree monocytes and eosinophils v3-CSBRP-May-2012
- 25. GROWTH FACTORS • Platelet derived growth factor - PGDF • Transforming growth factor β – Chemokines - Leukocytes and Mesenchymal Cells • Important in regeneration and repair v3-CSBRP-May-2012
- 26. LYSOSOMAL CONSTITUENTS • Neutrophils, Monocyte/Macrophages – Enzymes and proteins within granules • Cationic proteins – ↑ vascular permeability – Chemotactic • Neutral proteases – Degrade ECM v3-CSBRP-May-2012
- 27. Plasma derived mediators PLASMA PROTEASES 3 interrelated systems are active within this category 1. Kinin system Highly vasoactive 2. Complement system Vasoactive Chemotactic 3. Clotting system Vasoactive Cleaves C3 v3-CSBRP-May-2012
- 29. BRADYKININ • Released by activated Hageman factor (XIIa) • Bradykinin • Release of vasoactive nonapeptide bradykinin • Generated from the plasma HMWK • Potent vasodilator • Increased vascular permeability • Contraction of smooth muscle PAIN • Produce pain • Stimulates release of histamine • Activates the arachidonic acid cascade v3-CSBRP-May-2012
- 30. IMPORTANT NOTE Activated Hageman factor (factor XIIA) initiates the clotting, fibrinolytic and kinin systems The products of this initiation (kallikrein, factor XIIA, and plasmin, but particularly, kallikrein) can, by feedback, activate Hageman factor, resulting in significant amplification of the effects of the initial stimulus v3-CSBRP-May-2012
- 31. Complement system • Plasma proteins - act against microbial agents • Products of activated complement – Vascular permeability – Chemotaxis – Opsonization – Lysis v3-CSBRP-May-2012