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

3. 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

4. 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

5. ACUTE INFLAMMATION “PROTECTIVE” RESPONSE NON -specific

6. ACUTE INFLAMMATION VASCULARVASCULAR EVENTS CELLULARCELLULAR EVENTS (PMN or P oly M orphonuclear N eutrophil, Leukocyte?, “POLY”, Neutrophil, Granulocyte, Neutrophilic Granulocyte “MEDIATORS”“MEDIATORS”

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

8. RuborCalorTumorDolor 5 th (functio laesa) HISTORICAL HIGHLIGHTS (Egypt, 3000 BC)

9. STIMULI for acute inflammation INFECTIOUSINFECTIOUS PHYSICALPHYSICAL CHEMICALCHEMICAL Tissue Necrosis Foreign Bodies (FBs) Immune “responses”, or “complexes”

10. Vascular Changes Changes in Vascular Flow and Caliber Increased Vascular Permeability

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

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

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

14. ADHESION MOLECULES (glycoproteins) affecting ADHESION and TRANSMIGRATION SECRETINS (from endothelial cells) INTEGRINS (from many cells)

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

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

17. PHAGOCYTOSIS RECOGNITION ENGULFMENT KILLING (DEGRADATION/ DIGESTION)

18. CHEMICAL MEDIATORS From plasma or cellsFrom plasma or cells Have “triggering” stimuliHave “triggering” stimuli Usually have specific targetsUsually have specific targets Can cause a “cascade”Can cause a “cascade” Are short livedAre short lived

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

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

21. SEROTONIN (5HT, 5 - H ydroxy- Tryptamine ) Platelets and EnteroChromaffin Cells Also vasodilatation, but more indirect Evokes N.O. synthetase (a ligase) from argenine

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

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

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

26. EICOSANOIDS (ARACHIDONIC ACID DERIVATIVES) Part of cell membranes 1) Prostaglandins1) Prostaglandins (incl. Thromboxanes) 2) Leukotrienes2) Leukotrienes 3) Lipoxins3) Lipoxins (new) MULTIPLE ACTIONS AT MANY LEVELS

28. Prostaglandins (thromboxanes included) Pain Fever Clotting

29. Leukotrienes Chemotaxis Vasoconstriction Increased Permeability

30. Lipoxins INHIBIT chemotaxis Vasodilatation Counteract actions of leukotrienes

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

32. 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), e.g., CXC, CC, CX3C, XC families, PF-4, IL-8

33. N ITRIC O XIDE Potent vasodilator Produced from the action of nitric oxide synthetase from arginine

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

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

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

37. OUTCOMES OF ACUTE INFLAMMATION 1) 100% complete RESOLUTION 2) SCAR 3)CHRONIC inflammation

38. Morphologic PATTERNS of Acute INFLAMMATION (EXUDATE) SerousSerous (watery) FibrinousFibrinous (hemorrhagic, rich in FIBRIN) SuppurativeSuppurative (PUS) UlcerativeUlcerative

39. BLISTER, “Watery”, i.e., SEROUS

40. FIBRINOUS

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

42. PURULENT, FIBRINOPURULENT

43. ULCERATIVE

44. 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

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

46. CAUSES of CHRONIC INFLAMMATION 1) PERSISTENCE of Infection 2) PROLONGED EXPOSURE to insult 3) AUTO-IMMUNITY

47. Cellular Players LYMPHOCYTESLYMPHOCYTES MACROPHAGESMACROPHAGES (aka, HISTIOCYTES) PLASMA CELLS EOSINOPHILS MAST CELLS

48. MORPHOLOGY INFILTRATION TISSUE DESTRUCTION HEALING

49. GRANULOMAS GRANULOMATOUS INFLAMMATION 4 COMPONENTS FIBROBLASTS LYMPHSHISTIOS “GIANT” CELLS

50. GRANULOMAS GRANULOMATOUS INFLAMMATION CASEATING (TB) NON-CASEATING

51. LYMPHATIC DRAINAGE SITE  REGIONAL LYMPH NODES

52. SYSTEMIC MANIFESTATIONS (NON-SPECIFIC) FEVER, CHILLS C-Reactive Protein (CRP) “Acute Phase” Reactants, i.e., α1-α2 Erythrocyte Sedimentation Rate (ESR) increases Leukocytosis Pulse, Blood Pressure Cytokine Effects, e.g., TNF(α), IL-1

53. NORMAL SPE Serum Protein Electrophoresis In ACUTE Inflammation Alpha-1 & alpha-2 are increased, i.e., “acute phase” reactants.