Subject: General Pathology Chapter: Inflammation

1. Inflammation Dr Omar Chughtai

2. Tissue Response to Injury

4. Inflammation Triggers: Infectious organisms Trauma Objectives: Remove the trigger Remove any dead tissue End Result: Resolves when harmful stimulus is eliminated As Inflammation ends, Repair starts

5. Inflammation Protective in nature Removes harmful agents Enables tissue to heal May itself be harmful Too much Misdirected

6. The Cardinal Signs of Inflammation Rubor (redness) Tumor (swelling) Calor (heat) Dolor (pain) Functio Laesa (loss of function)

7. The Cardinal Signs of Inflammation

8. Inflammation Acute Rapid onset Short duration Neutrophils Exudation of fluid and plasma proteins Inflammation followed by Repair Chronic Slow onset; may follow acute Longer duration Lymphocytes and Macrophages Proliferation of blood vessels Simultaneous Inflammation and Repair

9. Acute Inflammation - Triggers Infections - Organisms and their toxins Tissue Necrosis - Ischemia, Chemical injury Foreign Bodies - Traumatic tissue injury Immune Reactions - Hypersensitivity

10. Acute Inflammation Changes in Vascular Caliber and Flow Increased Vascular Permeability Emigration of Leukocytes

11. Acute Inflammation Blood vessels Increased caliber Increased permeability Leukocytes Recruitment Chemotaxis Phagocytosis

12. Vasodilation Initial transient vasoconstriction of arterioles Histamine and NO act on vascular smooth muscle Vasodilation follows after a few seconds Increased blood flow in the area Opening of new capillary beds

13. Increased Vascular Permeability Retraction of endothelial cells Histamine, Bradykinin, NO, Substance P Endothelial injury Direct damage from burns Infectious organisms Neutrophils

14. Increased Vascular Permeability

15. Leukocyte Recruitment

16. Leukocyte Recruitment Margination: Slow blood flow White cells redistribute along periphery of lumen

17. Leukocyte Recruitment Rolling: Mediated by Selectins and their Ligands Histamine and Thrombin: Induce P-Selectin expression TNF and IL-1: Induce E-selectin and L-Selectin ligand Leukocytes: Express L-selectin and Ligand for E and P Selectins

18. Leukocyte Recruitment Activation: Chemokines (IL-8, PAF) activate leukocytes Integrins (VLA-4, LFA-1) converted to high affinity states

19. Leukocyte Recruitment Adhesion: Mediated by Integrins and their Ligands TNF, IL-1: Induce endothelial expression of ligands for Integrins VLA-4: VCAM-1 LFA-1: ICAM-1

20. Leukocyte Recruitment Diapedesis: Chemokines stimulate adherant leukocytes to migrate through inter-endothelial spaces PECAM-1 (CD31)

21. Leukocyte Recruitment

22. Chemotaxis Movement along a chemical gradient Leukocytes adhere to surrounding tissue cells Extend flopodia in the direction of movement Chemotactic agents: Exogenous: Bacterial products Endogenous: IL-8 C5a LTB4

23. Recognition

24. Recognition Toll-like Receptors for Microbial Products Bind bacterial lipopolysaccharides, proteoglycans and lipids, and double stranded RNA (viral product) Stimulate production of mediators and microbicidal substances G Protein-coupled Receptors Bind bacterial peptides containing N-formylmethionyl residues Bind chemokines, complement proteins (C5a) and PAF Convert Integrin to high affinity state Stimulate chemotaxis

25. Recognition Receptors for Opsonins IgG specific for the particle Complement proteins (C3) Facilitate phagocytosis of microbes Receptors for Cytokines IFN-ɣ Cause production of microbicidal substances

26. Recognition

27. Engulfment

28. Killing of Microbes

30. Termination Stop signals (Switch in AA metabolism) Anti-inflammatory cytokines (IL-10, TGF-ß) Anti-inflammatory mediators (Resolvins, Protectins) Neutrophils have limited lives in tissue; die by apoptosis within a few hours after leaving blood vessel

32. Leukocyte-Induced Injury

33. Defects in Leukocyte Function

36. Mediators of Inflammation Origin Cells or Plasma Proteins Preformed or Synthesized Activation In response to various triggers Amplification One mediator can stimulate release of others Actions Different effects on different cells Deactivation Inactivated / Decay / Inhibited quickly

37. Mediators of Inflammation Cell Derived Vasoactive Amines AA Metabolites PAF ROS NO Cytokines Chemikines Lysosomal Enzymes Neuropeptides Plasma Proteins Complement System Coagulation Pathway Kinin System

38. Vasoactive Amines - Histamine Preformed in Mast cells and Basophils Triggers Physical injury Ab’s binding to Mast cells Complement Proteins (C3a, C5a) Effects: Dilation of arterioles Increased permeability of venules (interendothelial gaps)

39. Vasoactive Amines - Serotinin Preformed in platelets Trigger for release: Platelet aggregation after contact with collagen Effect: Increased vascular permeability

40. Arachidonic Acid Metabolites Arachidonic Acid: 20-C Polyunsaturated Fatty Acid Normally esterified in membrane phospholipids Physical/Chemical injury activates Phospholipase A2 Releases AA from the membrane Metabolism through two pathways Cyclooxygenase Pathway Lipoxygenase Pathway AA-derived mediators act through G-Protein coupled receptors

42. Platelet Activating Factor Originally described as a factor that causes platelet aggregation Released by: Platelets, Endothelial cells, Basophils, Mast Cells Effects: Vasodilation Increased vascular permeability Increased leukocyte ashesion Chemotaxis Oxidative burst

43. Reactive Oxygen Species Oxygen derived free radicals may be released extra-cellularly Production depends on Phagocyte Oxidase Effects: Endothelial damage, leading to Increased vascular permeability Injury to interstitial cells Inactivation of Anti-Proteases Anti-oxidants: Superoxide dismutase Catalase Ceruloplasmin Transferrin

44. Nitric Oxide

45. Cytokines - TNF and IL-1

46. Chemokines Small (8-10kD) proteins Diverse actions depending on cell type Act as chemoattractants 40 different chemokines in 4 groups 20 different receptors CXCR-4 and CCR-5 receptors are site of entry of HIV

47. Neuropeptides - Substance P Transmission of pain signals Regulation of blood pressure Increased vascular permeability

48. Lysosomal Enzymes

49. Plasma Proteins Complement Proteins Coagulation Factors Kinin Proteins

50. Plasma Proteins - Complement System

51. Plasma Proteins - Complement System

53. Coagulation and Kinin Systems Exposed Collagen activates Factor XII Extrinsic pathway starts Thrombin binds PAR1 Receptors Mobilization of P selectin Increased recruitment of leukocytes Induction of COX-2

54. Coagulation and Kinin Systems Kallikerin Activates Factor XII Chemotactic Bradykinin Activates Factor XII Increased vascular permeability Vasodilation Plasmin Activates Factor XII Lysis of fibrin clots Cleaves C3 to produce C3 fragments

56. Chronic Inflammation Inflammation for a prolonged period (weeks-months) Onset After Acute Inflammation When injurious agent is not removed promptly More and more inflammatory cells are recruited to site of injury Insideous Onset Low intensity injury for long period of time Inflammatory response is not overwhelming Injury and inflammation persist

57. Chronic Inflammation - Causes Persistent infection MTB Viruses Fungi Parasites Immune mediated Autoimmune diseases (Rheumatoid arthritis) Allergic diseases (Broncial asthma) Prolonged exposure Silicosis (Pulmonary fibrosis)

58. Chronic Inflammation - Features Inflammatory infiltrate Macrophages Lymphocytes Plasma Cells Tissue destruction Persistent injury Inflammatory cells and Mediators Repair Angiogenesis Fibrosis

61. Chronic Inflammation - Cells Macrophages Lymphocytes Plasma Cells Eosinophils Mast Cells Neutrophils!

62. Maturation of Macrophages

65. Chronic Inflammation - Cells Plasma Cells Develop from activated B lymphocytes Produce Ab’s against the target Ag Eosinophils IgE mediated immune reactions (Allergy) Parasitic infections Recruited by eotaxin Granules contain Major Basic Protein (Toxic to parasites)

67. Chronic Inflammation - Cells Mast Cells Bind Fc portion of IgE Ab Degranulation when cell bound IgE Ab binds Ag Release Histamine, Serotinin Allergic reactions to food, drugs Neutrophils Persistent microbes (Osteomyelitis) Repeated injury (Lung damage due to smoking)

70. Foreign Body Granuloma Inert foreign bodies Talc Sutures Foreign Body-type Giant Cells Haphazardly arranged nuclei

71. Immune Granuloma - TB

72. Immune Granuloma - Sarcoidosis

73. Systemic Effects of Inflammation Fever Induced by pyrogens Leukocytes release IL-1, TNF upon activation IL-1, TNF induce Cyclooxygenase; PG produced PGE2 stimulates production of cAMP in hypothalamus Temperature set point is reset to a higher level

74. Systemic Effects of Inflammation Acute Phase Proteins upregulated C Reactive Protein and Serum Amyloid A Protein Bind microbial cell walls; act as opsonins Serum Amyloid A Protein Faciltates transport of HDL to macrophages Fibrinogen Binds red cells and causes rouleaux formation Leads to increased ESR

75. Systemic Effects of Inflammation Leukocytosis Leukemoid reaction with Left Shift Lymphocytosis Leukopenia Eosinophilia

76. The Cardinal Signs of Inflammation

86. Thank You!