Inflammation an overview

1. Inflammationan overview Hal Hawkins, Ph.D.,M.D. Fundamentals of Inflammation Course, BBSC 6210 June 25, 2012

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

3. MICROVASCULAR ENDOTHELIAL CELL

4. Histamine

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

8. Triple Response of Lewis:

10. 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 Vascular reactions account for the classical cardinal signs of inflammation:

14. Time course of acute inflammation

15. MARGINATION ADHERENCE EMIGRATION AND CHEMOTAXIS Neutrophil Recruitment:

16. Julius Cohnheim, 1839-1884

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

18. “With the slowing of blood flow in the dilated venules leukocytes appear in the marginal stream and tend to stick to the vessel walls. At first the leukocytes stick momentarily and are then displaced to be washed away by the blood stream.“ OBSERVATIONS OF COHNHEIM(1882)

19. “As they begin to adhere more closely some are pushed slowly along by the blood stream, becoming flattened and elongated in the direction of the flow so that they have the appearance of blobs of jelly being pushed along over a sticky surface.” more COHNHEIM:

20. “Gradually some of the cells adhere more firmly until even a relatively swift stream of plasma and red corpuscles cannot dislodge them. With an adequate injury some of the leukocytes sticking to the wall begin to make their way through it by active movements, taking 2 to 12 minutes to do so. “ more COHNHEIM:

22. Will this link work?http://www.youtube.com/watch?v=WEGGMaRX8f0

24. Selectins(responsible for rolling)

25. Integrins(essential for firm adhesion and emigration)

26. Integrin activation

27. Armond Goldman’s discovery of neutrophil integrins Armond Goldman’s discovery of integrins

29. http://www.youtube.com/watch?v=9wxK6oLA5oc And another one in color!

30. http://www.youtube.com/watch?v=DMvixApKzKs And a third in diagram form

31. Transient opening of intercellular junctions

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

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

34. Platelet-Activating Factor, PAF

35. Chemotaxis: Migration toward higher concentration

36. http://www.youtube.com/watch?v=ZUUfdP87Ssg http://www.youtube.com/watch?v=ZUUfdP87Ssg

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

38. Relative potencies of chemotactic factors

39. Priorities among chemotactic factors

40. COMPLEMENT:a central mediator of inflammation and immunity

41. Complement components

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

44. Opsonizationby complementstimulates phagocytosis

45. Phagocytosis

46. The Neutrophil Oxidative Burst

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

48. Pneumonia

49. 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 MEDIATORS of INFLAMMATION: