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Inflammation an overview

Inflammation an overview. Hal Hawkins, Ph.D.,M.D. Basic Human Pathobiology Course, PATH 6266 May 10, 20010. Inflammation has been defined as the reaction to injury of vascularized tissue. ACUTE INFLAMMATION includes:. Vasodilation and vascular leakage Cellular: Recruitment

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Inflammation an overview

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  1. Inflammation an overview Hal Hawkins, Ph.D.,M.D. Basic Human Pathobiology Course, PATH 6266 May 10, 20010

  2. Inflammation has been definedas the reaction to injuryof vascularized tissue.

  3. ACUTE INFLAMMATION includes: Vasodilation and vascular leakage Cellular: Recruitment Activation Functions Tissue Injury

  4. MICROVASCULAR ENDOTHELIAL CELL

  5. Histamine

  6. Leakage of venules marked with colloidal carbon(India ink) after application of histamine

  7. Triple Response of Lewis:

  8. Vascular reactions account for the classical cardinal signs of inflammation: • Tumor – edema due to plasma leakage • Rubor – dilation of arterioles and engorgement of microvasculature • Calor – increased local temperature • Dolor –probably due to stretching and prostaglandins

  9. Julius Cohnheim, 1839-1884

  10. Time course of acute inflammation

  11. Neutrophil Recruitment: MARGINATION ADHERENCE EMIGRATION AND CHEMOTAXIS

  12. Experiments of Cohnheim: The tongue of the frog provides an opportunity to see the microcirculation and the movements of neutrophils.

  13. Selectins(responsible for rolling)

  14. Integrins(essential for firm adhesion and emigration)

  15. Integrin activation, in detail

  16. Transient opening of intercellular junctions

  17. ADHESION and TRANSMIGRATION: • Redistribution of adhesion molecules to the neutrophil cell surface: • P-selectin from endothelial granules • Mac-1 (CD11b/CD18) from neutrophil granules • Increased avidity of binding of Mac-1 and LFA-1, another neutrophil integrin: “activation of integrins” • Induction of adhesion molecules on endothelium: • E-selectin, ICAM-1, VCAM-1

  18. Neutrophil emigration does not produce vascular leakage! (from Marchesi and Florey)

  19. Neutrophil Activation: • Receptors (complement, IgG, etc.) • PAF (platelet activating factor) • Phospholipase  Inositol triphosphate  Ca++ release Diacylglycerol  Protein kinase C

  20. Platelet-Activating Factor, PAF

  21. Chemotaxis: Migration toward higher concentration

  22. Important chemotactic factors: • Complement fragment C5a • Bacterial formylated peptides • Arachidonic acid products, e.g. Leukotriene B4 • Cytokines, e.g. IL-8

  23. Relative potencies of chemotactic factors

  24. Priorities among chemotactic factors

  25. COMPLEMENT:a central mediator of inflammation and immunity

  26. Complement components

  27. From Abbas’ textbook

  28. Neutrophil Functions: • PHAGOCYTOSIS • FUSION OF GRANULES • BACTERIAL KILLING

  29. Opsonizationby complementstimulates phagocytosis

  30. Phagocytosis

  31. The Neutrophil Oxidative Burst

  32. Bacterial Killing: • O2-, superoxide • H2O2, peroxide • HOCl, hypochlorous acid  • OH•, hydroxyl radical • Acid hydrolases (enzymes) • Bactericidal proteins, defensins, lactoferrin, lysozyme

  33. MEDIATORS of INFLAMMATION: • Plasma proteases, e.g. complement • Vasoactive amines, e.g. histamine • Platelet-activating factor PAF • Arachidonic acid metabolites, e.g. prostaglandin E3 • Reactive oxygen and nitrogen species • Cytokines and chemokines, e.g. IL-8 • Neuropeptides and endothelin

  34. Prostaglandins and leukotrienes • Products of arachidonic acid metabolism • Potent vasodilators/vasoconstrictors • Cyclo-oxygenase (COX), needed for prostaglandin synthesis, is inhibited by aspirin and selective COX2 inhibitors including the notorious Vioxx • Important in fever and pain • Lipoxygenase leads to leukotrienes, proinflammatory lipids active in asthma

  35. Inflammatory Tissue Injury • O2-, superoxide • H2O2, peroxide • HOCl, hypochlorous acid • OH•, hydroxyl radical • ONOO-, peroxynitrite (reactive oxygen and nitrogen species) • Lysosomal neutral hydrolases

  36. Neutrophil apoptosis: • Follows emigration and phagocytosis • Minimizes tissue injury

  37. Regulation of neutrophil apoptosis • DELAY: • GM-CSF G-CSF • LPS, IL-1, IL-2 • IFN-gamma • STIMULATE: • IL-6 • Phagocytosis • Oxidative burst

  38. Apoptosis is the key to prevention of tissue injury • Cellular contents may not be released • Clearance by macrophages stimulates activation of macrophages to secrete factors favoring wound healing

  39. HEALING AFTER INJURY:Repair and fibrosis • Proliferation and migration of surviving cells • Depends on connective tissue matrix • GRANULATION TISSUE - “proud flesh” • Proliferating capillaries • Fibroblasts, migrating and proliferating • Follows inflammation, often coexists • CONTRACTS to close wound

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