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Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
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Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
Inflammation
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Inflammation
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Inflammation

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Subject: General Pathology …

Subject: General Pathology
Chapter: Inflammation

Published in: Health & Medicine
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  • 1. Inflammation<br />Dr Omar Chughtai<br />
  • 2. Tissue Response to Injury<br />
  • 3.
  • 4. Inflammation<br />Triggers:<br />Infectious organisms<br />Trauma<br />Objectives: <br />Remove the trigger<br />Remove any dead tissue <br />End Result: <br />Resolves when harmful stimulus is eliminated<br />As Inflammation ends, Repair starts<br />
  • 5. Inflammation<br />Protective in nature<br />Removes harmful agents <br />Enables tissue to heal<br />May itself be harmful<br />Too much <br />Misdirected<br />
  • 6. The Cardinal Signs of Inflammation<br />Rubor (redness)<br />Tumor (swelling)<br />Calor (heat)<br />Dolor (pain)<br />Functio Laesa (loss of function)<br />
  • 7. The Cardinal Signs of Inflammation<br />
  • 8. Inflammation<br />Acute<br />Rapid onset<br />Short duration<br />Neutrophils<br />Exudation of fluid and plasma proteins<br />Inflammation followed by Repair<br />Chronic<br />Slow onset; may follow acute<br />Longer duration<br />Lymphocytes and Macrophages<br />Proliferation of blood vessels<br />Simultaneous Inflammation and Repair<br />
  • 9. Acute Inflammation - Triggers<br />Infections - Organisms and their toxins<br />Tissue Necrosis - Ischemia, Chemical injury<br />Foreign Bodies - Traumatic tissue injury <br />Immune Reactions - Hypersensitivity<br />
  • 10. Acute Inflammation<br />Changes in Vascular Caliber and Flow<br />Increased Vascular Permeability<br />Emigration of Leukocytes<br />
  • 11. Acute Inflammation<br />Blood vessels<br />Increased caliber<br />Increased permeability<br />Leukocytes<br />Recruitment<br />Chemotaxis<br />Phagocytosis<br />
  • 12. Vasodilation <br />Initial transient vasoconstriction of arterioles<br />Histamine and NO act on vascular smooth muscle<br />Vasodilation follows after a few seconds<br />Increased blood flow in the area<br />Opening of new capillary beds<br />
  • 13. Increased Vascular Permeability <br />Retraction of endothelial cells<br />Histamine, Bradykinin, NO, Substance P<br />Endothelial injury<br />Direct damage from burns<br />Infectious organisms<br />Neutrophils<br />
  • 14. Increased Vascular Permeability <br />
  • 15. Leukocyte Recruitment<br />
  • 16. Leukocyte Recruitment<br />Margination: Slow blood flow<br />White cells redistribute along periphery of lumen<br />
  • 17. Leukocyte Recruitment<br />Rolling: Mediated by Selectins and their Ligands<br />Histamine and Thrombin: Induce P-Selectin expression <br />TNF and IL-1: Induce E-selectin and L-Selectin ligand<br />Leukocytes: Express L-selectin and Ligand for E and P Selectins<br />
  • 18. Leukocyte Recruitment<br />Activation: Chemokines (IL-8, PAF) activate leukocytes<br />Integrins (VLA-4, LFA-1) converted to high affinity states<br />
  • 19. Leukocyte Recruitment<br />Adhesion: Mediated by Integrins and their Ligands<br />TNF, IL-1: Induce endothelial expression of ligands for Integrins <br />VLA-4: VCAM-1<br />LFA-1: ICAM-1<br />
  • 20. Leukocyte Recruitment<br />Diapedesis: Chemokines stimulate adherant leukocytes to migrate through inter-endothelial spaces<br />PECAM-1 (CD31)<br />
  • 21. Leukocyte Recruitment<br />
  • 22. Chemotaxis<br />Movement along a chemical gradient<br />Leukocytes adhere to surrounding tissue cells<br />Extend flopodia in the direction of movement<br />Chemotactic agents: <br />Exogenous: Bacterial products<br />Endogenous: <br />IL-8<br />C5a<br />LTB4<br />
  • 23. Recognition<br />
  • 24. Recognition<br />Toll-like Receptors for Microbial Products<br />Bind bacterial lipopolysaccharides, proteoglycans and lipids, and double stranded RNA (viral product) <br />Stimulate production of mediators and microbicidal substances <br />G Protein-coupled Receptors<br />Bind bacterial peptides containing N-formylmethionyl residues<br />Bind chemokines, complement proteins (C5a) and PAF<br />Convert Integrin to high affinity state<br />Stimulate chemotaxis<br />
  • 25. Recognition<br />Receptors for Opsonins<br />IgG specific for the particle<br />Complement proteins (C3)<br />Facilitate phagocytosis of microbes<br />Receptors for Cytokines<br />IFN-ɣ<br />Cause production of microbicidal substances<br />
  • 26. Recognition<br />
  • 27. Engulfment<br />
  • 28. Killing of Microbes<br />
  • 29.
  • 30. Termination <br />Stop signals (Switch in AA metabolism)<br />Anti-inflammatory cytokines (IL-10, TGF-ß)<br />Anti-inflammatory mediators (Resolvins, Protectins)<br />Neutrophils have limited lives in tissue; die by apoptosis within a few hours after leaving blood vessel<br />
  • 31.
  • 32. Leukocyte-Induced Injury<br />
  • 33. Defects in Leukocyte Function<br />
  • 34.
  • 35.
  • 36. Mediators of Inflammation<br />Origin<br />Cells or Plasma Proteins<br />Preformed or Synthesized<br />Activation<br />In response to various triggers<br />Amplification<br />One mediator can stimulate release of others<br />Actions<br />Different effects on different cells<br />Deactivation<br />Inactivated / Decay / Inhibited quickly<br />
  • 37. Mediators of Inflammation<br />Cell Derived<br />Vasoactive Amines<br />AA Metabolites<br />PAF<br />ROS<br />NO<br />Cytokines<br />Chemikines<br />Lysosomal Enzymes<br />Neuropeptides<br />Plasma Proteins<br />Complement System<br />Coagulation Pathway<br />Kinin System<br />
  • 38. Vasoactive Amines - Histamine<br />Preformed in Mast cells and Basophils<br />Triggers<br />Physical injury<br />Ab’s binding to Mast cells<br />Complement Proteins (C3a, C5a)<br />Effects: <br />Dilation of arterioles<br />Increased permeability of venules (interendothelial gaps)<br />
  • 39. Vasoactive Amines - Serotinin<br />Preformed in platelets<br />Trigger for release: <br />Platelet aggregation after contact with collagen<br />Effect:<br />Increased vascular permeability<br />
  • 40. Arachidonic Acid Metabolites<br />Arachidonic Acid: 20-C Polyunsaturated Fatty Acid<br />Normally esterified in membrane phospholipids<br />Physical/Chemical injury activates Phospholipase A2 <br />Releases AA from the membrane <br />Metabolism through two pathways<br />Cyclooxygenase Pathway<br />Lipoxygenase Pathway<br />AA-derived mediators act through G-Protein coupled receptors<br />
  • 41.
  • 42. Platelet Activating Factor<br />Originally described as a factor that causes platelet aggregation<br />Released by: <br />Platelets, Endothelial cells, Basophils, Mast Cells<br />Effects: <br />Vasodilation<br />Increased vascular permeability<br />Increased leukocyte ashesion<br />Chemotaxis<br />Oxidative burst<br />
  • 43. Reactive Oxygen Species<br />Oxygen derived free radicals may be released extra-cellularly<br />Production depends on Phagocyte Oxidase<br />Effects: <br />Endothelial damage, leading to Increased vascular permeability<br />Injury to interstitial cells<br />Inactivation of Anti-Proteases<br />Anti-oxidants: <br />Superoxide dismutase<br />Catalase<br />Ceruloplasmin<br />Transferrin<br />
  • 44. Nitric Oxide<br />
  • 45. Cytokines - TNF and IL-1<br />
  • 46. Chemokines<br />Small (8-10kD) proteins<br />Diverse actions depending on cell type<br />Act as chemoattractants<br />40 different chemokines in 4 groups<br />20 different receptors<br />CXCR-4 and CCR-5 receptors are site of entry of HIV<br />
  • 47. Neuropeptides - Substance P<br />Transmission of pain signals<br />Regulation of blood pressure<br />Increased vascular permeability<br />
  • 48. Lysosomal Enzymes<br />
  • 49. Plasma Proteins<br />Complement Proteins<br />Coagulation Factors<br />Kinin Proteins<br />
  • 50. Plasma Proteins - Complement System<br />
  • 51. Plasma Proteins - Complement System<br />
  • 52.
  • 53. Coagulation and Kinin Systems<br />Exposed Collagen activates Factor XII<br />Extrinsic pathway starts<br />Thrombin binds PAR1 Receptors <br />Mobilization of P selectin <br />Increased recruitment of leukocytes<br />Induction of COX-2<br />
  • 54. Coagulation and Kinin Systems<br />Kallikerin<br />Activates Factor XII<br />Chemotactic<br />Bradykinin<br />Activates Factor XII<br />Increased vascular permeability<br />Vasodilation<br />Plasmin<br />Activates Factor XII<br />Lysis of fibrin clots<br />Cleaves C3 to produce C3 fragments<br />
  • 55.
  • 56. Chronic Inflammation<br />Inflammation for a prolonged period (weeks-months)<br />Onset <br />After Acute Inflammation<br />When injurious agent is not removed promptly<br />More and more inflammatory cells are recruited to site of injury<br />Insideous Onset<br />Low intensity injury for long period of time<br />Inflammatory response is not overwhelming<br />Injury and inflammation persist<br />
  • 57. Chronic Inflammation - Causes<br />Persistent infection <br />MTB<br />Viruses<br />Fungi<br />Parasites<br />Immune mediated<br />Autoimmune diseases (Rheumatoid arthritis)<br />Allergic diseases (Broncial asthma)<br />Prolonged exposure <br />Silicosis (Pulmonary fibrosis)<br />
  • 58. Chronic Inflammation - Features<br />Inflammatory infiltrate<br />Macrophages<br />Lymphocytes<br />Plasma Cells<br />Tissue destruction<br />Persistent injury<br />Inflammatory cells and Mediators<br />Repair<br />Angiogenesis<br />Fibrosis<br />
  • 59.
  • 60.
  • 61. Chronic Inflammation - Cells<br />Macrophages<br />Lymphocytes<br />Plasma Cells<br />Eosinophils<br />Mast Cells<br />Neutrophils!<br />
  • 62. Maturation of Macrophages<br />
  • 63.
  • 64.
  • 65. Chronic Inflammation - Cells<br />Plasma Cells<br />Develop from activated B lymphocytes<br />Produce Ab’s against the target Ag<br />Eosinophils<br />IgE mediated immune reactions (Allergy)<br />Parasitic infections<br />Recruited by eotaxin<br />Granules contain Major Basic Protein (Toxic to parasites)<br />
  • 66.
  • 67. Chronic Inflammation - Cells<br />Mast Cells<br />Bind Fc portion of IgE Ab<br />Degranulation when cell bound IgE Ab binds Ag<br />Release Histamine, Serotinin<br />Allergic reactions to food, drugs<br />Neutrophils<br />Persistent microbes (Osteomyelitis)<br />Repeated injury (Lung damage due to smoking)<br />
  • 68. Granulomatous Inflammation<br />Distinctive type of chronic inflammation<br />Attempt to contain an offending agent that is difficult to eradicate<br />Strong activation of T cells and Macrophages<br />Examples: <br /><ul><li>TB - Fungal Infection - Syphilis
  • 69. Leprosy - Sarcoidosis - Crohn’s</li></li></ul><li>Granuloma<br />Focus of chronic inflammation<br />May have central necrosis<br />Aggregation of macrophages that are transformed into epithelioid cells<br />Epithelioid cells fuse to form Giant Cells<br />Surrounded by lymphocytes and plasma cells<br />
  • 70. Foreign Body Granuloma<br />Inert foreign bodies<br />Talc<br />Sutures<br />Foreign Body-type Giant Cells<br />Haphazardly arranged nuclei<br />
  • 71. Immune Granuloma - TB<br />
  • 72. Immune Granuloma - Sarcoidosis<br />
  • 73. Systemic Effects of Inflammation<br />Fever<br />Induced by pyrogens<br />Leukocytes release IL-1, TNF upon activation<br />IL-1, TNF induce Cyclooxygenase; PG produced<br />PGE2 stimulates production of cAMP in hypothalamus<br />Temperature set point is reset to a higher level<br />
  • 74. Systemic Effects of Inflammation<br />Acute Phase Proteins upregulated<br />C Reactive Protein and Serum Amyloid A Protein<br />Bind microbial cell walls; act as opsonins<br />Serum Amyloid A Protein<br />Faciltates transport of HDL to macrophages<br />Fibrinogen <br />Binds red cells and causes rouleaux formation <br />Leads to increased ESR<br />
  • 75. Systemic Effects of Inflammation<br />Leukocytosis <br />Leukemoid reaction with Left Shift<br />Lymphocytosis<br />Leukopenia<br />Eosinophilia<br />
  • 76. The Cardinal Signs of Inflammation<br />
  • 77.
  • 78.
  • 79.
  • 80.
  • 81.
  • 82.
  • 83.
  • 84.
  • 85.
  • 86. Thank You!<br />

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