Inflammation an overview

1. Inflammation an overview Hal Hawkins, Ph.D.,M.D. Basic Human Pathobiology Course, PATH 6266 May 7, 2012

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

3. ACUTE INFLAMMATION includes: 1) Vasodilation and vascular leakage 2) Cellular: recruitment activation functions tissue Injury

4. MICROVASCULAR ENDOTHELIAL CELL

6. Histamine

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

9. Triple Response of Lewis:

11. 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

15. Time course of acute inflammation

16. Neutrophil Recruitment: MARGINATION ADHERENCE EMIGRATION AND CHEMOTAXIS

17. Julius Cohnheim, 1839-1884

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

22. Selectins(responsible for rolling)

23. Integrins(essential for firm adhesion and emigration)

24. Integrin activation

25. Transient opening of intercellular junctions

26. 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

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

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

29. Platelet-Activating Factor, PAF

30. Chemotaxis: Migration toward higher concentration

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

32. Relative potencies of chemotactic factors

33. Priorities among chemotactic factors

34. COMPLEMENT:a central mediator of inflammation and immunity

35. Complement components

37. From Abbas’ textbook

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

39. Opsonizationby complementstimulates phagocytosis

40. Phagocytosis

41. The Neutrophil Oxidative Burst

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

43. Pneumonia

44. 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

45. 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

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

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

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

49. 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

50. What’s new? Recognition of Pathogen Activated Molecular Pathways (PAMPs) including Toll Like Receptors, and Damage Activated Molecular Pathways (DAMPs) (together sometimes called Alarmins). TLR’s stimulate release of multiple pro-inflammatory peptides. DAMPs lead to assembly of inflammasomes, activation of caspase-1, and production of IL-1beta.