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CHAPTER 2

CHAPTER 2. Inflammation (5 OBJECTIVES) 1) (Concept) Understand the chain, progression, or sequence of vascular and cellular events in the histologic evolution of acute inflammation. 2) ( Rote ?) Learn the roles of various “chemical mediators” of acute inflammation

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CHAPTER 2

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  1. CHAPTER 2 Inflammation (5 OBJECTIVES) 1) (Concept) Understand the chain, progression, or sequence of vascular and cellular events in the histologic evolution of acute inflammation

  2. 2) (Rote?) Learn the roles of various “chemical mediators” of acute inflammation 3) Know the three possible outcomes of acute inflammation 4) Visualize the morphologic patterns of acute inflammation 5) Understand the causes, morphologic patterns, principle cells, minor cells, of chronic and granulomatous inflammation

  3. SEQUENCE OF EVENTS • NORMAL HISTOLOGY  • VASODILATATION  • INCREASED VASCULAR PERMEABILITY  • LEAKAGE OF EXUDATE  • MARGINATION, ROLLING, ADHESION  • TRANSMIGRATION (DIAPEDESIS)  • CHEMOTAXIS  • PMN ACTIVATION  • PHAGOCYTOSIS: Recognition, Attachment, Engulfment, Killing (degradation or digestion)  • TERMINATION  • 100% RESOLUTION, SCAR, or CHRONIC INFLAMMATION are the three possible outcomes

  4. ACUTE INFLAMMATION • “PROTECTIVE” RESPONSE (Evolutionary?) • NON-specific

  5. ACUTE INFLAMMATION • VASCULAR EVENTS • CELLULAR EVENTS (PMN or PolyMorphonuclearNeutrophil, Leukocyte?, “POLY”, Neutrophil, Granulocyte, Neutrophilic Granulocyte ONE CELL!!!!! • “MEDIATORS”

  6. ACUTE INFLAMMATION Neutrophil Polymorphonuclear Leukocyte, PMN, PML “Leukocyte” Granulocyte, Neutrophilic granulocyte “Poly-” Polymorph

  7. HISTORICAL HIGHLIGHTS (Egypt, 3000 BC) Rubor Calor Tumor Dolor 5th(functio laesa)

  8. STIMULI for acute inflammation • INFECTIOUS (B>V) • PHYSICAL • CHEMICAL • Tissue Necrosis • Foreign Bodies (FBs) • Immune “responses”, or “complexes”, but usually CHRONIC

  9. Vascular Changes • Changes in Vascular Flow and Caliber • Increased Vascular Permeability

  10. INCREASED PERMEABILITY • DILATATION • Endothelial “gaps” • Direct Injury • Leukocyte Injury • Transocytosis (endo/exo) • New Vessels

  11. LEAKAGE OF PROTEINACEOUS FLUID (EXUDATE, NOT TRANSUDATE)

  12. EXTRAVASATION of PMNs • MARGINATION(PMN’s go toward wall) • ROLLING(tumbling and HEAPING) • ADHESION • TRANSMIGRATION(DIAPEDESIS)

  13. ADHESION MOLECULES (CAMs)(glycoproteins) affectingADHESION and TRANSMIGRATION • SELECTINS (from endothelial cells): L,P,E • INTEGRINS (from many cells): ~8 types

  14. CHEMOTAXIS PMNs going to the site of “injury” AFTER transmigration

  15. LEUKOCYTE“ACTIVATION” • “triggered” by the offending stimuli for PMNs to: • 1) Produce eicosanoids (arachidonic acid derivatives, 20 carbon chains) • Prostaglandin (and thromboxanes) • Leukotrienes • Lipoxins • 2) Undergo DEGRANULATION • 3) Secrete CYTOKINES

  16. PHAGOCYTOSIS • RECOGNITION • ENGULFMENT • KILLING (DEGRADATION/DIGESTION)

  17. CHEMICAL MEDIATORS • From plasma or cells • Have “triggering” stimuli • Usually have specific targets • Can cause a “cascade” • Are short lived • Many are α-1 and α-2!

  18. HISTAMINE SEROTONIN COMPLEMENT KININS CLOTTING FACTORS EICOSANOIDS NITRIC OXIDE PLATELET ACTIVATING FACTOR (PAF) CYTOKINES /CHEMOKINES LYSOSOME CONSTITUENTS FREE RADICALS NEUROPEPTIDES CLASSIC MEDIATORS

  19. HISTAMINE • Mast Cells, basophils • POWERFUL Vasodilator • Vasoactive “amine” • IgE on mast cell

  20. SEROTONIN • (5HT, 5-Hydroxy-Tryptamine) • Platelets and EnteroChromaffin Cells • Also vasodilatation, but more indirect • Evokes N.O. synthetase (a ligase)

  21. COMPLEMENT SYSTEM • >20 components, in circulating plasma • Multiple sites of action, but LYSIS is the underlying theme CASCADE!!!

  22. KININ SYSTEM • BRADYKININ is KEY component, 9 aa’s • ALSO from circulating plasma • ACTIONS • Increased permeability • Smooth muscle contraction, NON vascular • Produces PAIN !!!

  23. CLOTTING FACTORS • Also from circulating plasma • Coagulation, i.e., production of fibrin • Fibrinolysis

  24. EICOSANOIDS(ARACHIDONIC ACID DERIVATIVES) • Part of cell membranes • 1) Prostaglandins (incl. Thromboxanes) • 2) Leukotrienes • 3) Lipoxins (new) MULTIPLE ACTIONS AT MANY LEVELS

  25. Prostaglandins(thromboxanes included) • Pain • Fever • Clotting

  26. Leukotrienes • Chemotaxis • Vasoconstriction • Increased Permeability

  27. Lipoxins • INHIBIT chemotaxis • Vasodilatation • Counteract actions of leukotrienes

  28. Platelet-Activating Factor(PAF) • Phospholipid • From MANY cells, like eicosanoids • ACTIVATE PLATELETS, powerfully

  29. CYTOKINES/CHEMOKINES • CYTOKINES are PROTEINS produced by MANY cells, but usually LYMPHOCYTES and MACROPHAGES, numerous roles in acute and chronic inflammation • TNFα, IL-1, by macrophages • CHEMOKINES are small proteins which are attractants for PMNs (>40)

  30. NITRIC OXIDE • Potent vasodilator • Produced from the action of nitric oxide synthetase from arginine

  31. PRIMARY Also called AZUROPHILIC, or NON-specific Myeloperoxidase Lysozyme (Bact.) Acid Hydrolases SECONDARY Also called SPECIFIC Lactoferrin Lysozyme Alkaline Phosphatase Collagenase LYSOSOMAL CONSTITUENTS

  32. FREE RADICALS • O2–(SUPEROXIDE) • H2O2(PEROXIDE) • OH- (HYDROXYL RADICAL) • VERY VERY DESTRUCTIVE

  33. NEUROPEPTIDES • Produced in CNS (neurons) • SUBSTANCE P • NEUROKININ A

  34. OUTCOMES OFACUTE INFLAMMATION • 1) 100% complete RESOLUTION • 2) SCAR • 3)CHRONIC inflammation

  35. Morphologic PATTERNSof Acute INFLAMMATION(EXUDATE) • Serous (watery) • Fibrinous (hemorrhagic, rich in FIBRIN) • Suppurative (PUS) • Ulcerative

  36. BLISTER, “Watery”, i.e., SEROUS

  37. FIBRINOUS

  38. PUS = PURULENT ABSCESS = POCKET OF PUS = NEUTROPHILS

  39. PURULENT, FIBRINOPURULENT

  40. ULCERATIVE

  41. SEQUENCE OF EVENTS • NORMAL HISTOLOGY  • VASODILATATION  • INCREASED VASCULAR PERMEABILITY  • LEAKAGE OF EXUDATE  • MARGINATION, ROLLING, ADHESION  • TRANSMIGRATION (DIAPEDESIS)  • CHEMOTAXIS  • PMN ACTIVATION  • PHAGOCYTOSIS: Recognition, Attachment, Engulfment, Killing (degradation or digestion)  • TERMINATION  • 100% RESOLUTION, SCAR, or CHRONIC inflammation

  42. CHRONIC INFLAMMATION (MONOS) “MONO”CYTE MACROPHAGE HISTIOCYTE LYMPHOCYTE

  43. CAUSES ofCHRONIC INFLAMMATION • 1) PERSISTENCE of Infection • 2) PROLONGED EXPOSURE to insult • 3) AUTO-IMMUNITY

  44. Cellular Players • LYMPHOCYTES • MACROPHAGES (aka, HISTIOCYTES) • PLASMA CELLS • EOSINOPHILS • MAST CELLS

  45. MORPHOLOGY • INFILTRATION • TISSUE DESTRUCTION • HEALING • FIBROSIS (SCARRING)

  46. GRANULOMASGRANULOMATOUS INFLAMMATION 4 COMPONENTS FIBROBLASTS LYMPHS “HISTIOS” “GIANT” CELLS

  47. GRANULOMASGRANULOMATOUS INFLAMMATION CASEATING (TB) NON-CASEATING

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