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UIC PCOL 425 - Anti-inflammatory agents

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Anti-inflammatory agents PCOL 502DR. JOHN O’BRYANEmail: [email protected] COMRBAssigned reading: Rang (6th edition), Chapter 13: pages 202-213 (optional background) inflammatory & immune responses and mediators Rang, Chapter 14: pages 226-245 NSAID, anti-rheumatoid drugs, immunosuppressant drugs, drugs used in gout Katzung (10th edition), Chapter 36: pages 573-597 1Inflammation•evolutionarily conserved response•primarily a defense mechanism, not a disease•role is to restore normal function to infected or damaged tissue•if healing incomplete ! chronic inflammation21. Acute inflammation autocoids, innate responses 2. Immune responseadaptive immune response: induction and effector phases 3. Chronic inflammation results if injurious agent persistsInflammation can be beneficial and/or destructive !clear infections"hypersensitivity reactions "autoimmune diseases Three phases to inflammation3Acute inflammatory response (initial response to tissue injury induced by a pathogen or noxious substance) 1. Chemical mediators or autocoids (bradykinin, serotonin, histamine, NO, prostaglandins, leukotrienes, ILs) 2. Vascular system (flow and permeability changes due to PGs, histamine, PAF and cytokine release) 3. Migration of blood cells, chemotaxis (neutrophils, mast cells, NK cells) 4. Innate response5. Time course is minutes to hours Inflammatory response4Innate response •non-adaptive, primordial response•evolutionarily conserved •some aspects are non-immunological•some comprise innate immune response-”knee-jerk” reaction of immune system •role in preventing host damage by adaptive responseAdaptive immune response •induced following recognition of pathogen by innate system•pathogen specific responses•backup systems in placeInflammatory Reactions 5Inflammatory response (con’t)Innate immune response•initiating event is pattern recognition - TOLL-like receptors•pathogen-associated molecular patterns (PAMPs)-specific to classes of pathogens-e.g. peptidoglycans, bacterial lipopolysaccharides-bind TLRs on antigen presenting cells, dendritic cells, & macrophages•TLR binding stim. response by APC or Macrophages-secretion of pro-inflammatory mediators-PGs and histamine release-!vascular permeability-exudation of factors !inflammatory response6Innate immune response•Natural or native immunity•Rapid response to microbes•physical and chemical barriers•Phagocytic cells (neutrophils &macrophages) and NK cells•Blood proteins & other mediators•Cytokines•Increase in vascular permeability3II. Immune response or subacute inflammation(immune competent cell activation)1. Innate and adaptive responses to antigeninnate: recognition by tissue M! of specific pathogen-associated molecular patterns (PAMPs)adaptive: induction and effector phase of both cellmediated and humoral mediated respose2. Can be beneficial and/or destructive hypersensitivity reactions autoimmune diseasesInflammatory response (con’t)Innate immunity• Natural or native immunity• Rapid response to microbes• Physical and chemical barriers• Phagocytic cells (neutrophils andmacrophages) and NK cells• Blood proteins (complementsystem) and other mediators• Cytokines: secreted proteinsthat regulate and control cells ofthe immune system• Increase in vascular permeability74Adaptive Immunity• Specific or acquiredimmunity• Exquisite specificityfor a large diversityof distinct foreignantigens• Memory and robustresponse to 2ndexposure• Lymphocytes andtheir products (Tand B cells)Immune SystemInnate ImmunityRapid kineticsNonspecific responseBaseline responseMediated by phagocytes,physical and chemicalbarriers, blood proteinsAdaptive ImmunitySlower kineticsSpecific responseIncrease response withrepeat exposureMediated by lymphocytesand their products (Band T cells)Adaptive immune response •Specific or acquired immunity•sustained response of organism to infection•Exquisite specificity for large diversity of foreign antigens•Memory and robust response to 2nd exposure•Lymphocytes (T and B cells) and their products8Immune System•Rapid kinetics•non-specific response•baseline responsemediated by phagocytes, physical and chemical barriers, and blood proteins•Slower kinetics•specific response•!response with !exposuremediated by lymphocytes (T and B cells) and their products Innate Immunity Adaptive Immunity9ADAPTIVE IMMUNE RESPONSEKey players - lymphocytes•B cells - produce antibodies•T cells - responsible for induction phase of immune response and cell-mediated immune rxns•NK cells - specialized lymphoid cells, active in non-immunological, innate response10ADAPTIVE IMMUNE RESPONSEResponse occurs in two phases1. induction phase - •antigen presented to T cells by dendritic cell, •T cells interact with other T and B cells, •clonal expansion of cells that recognize antigen2. effector phase - •antigen-recognizing B cells differentiate into plasma cells→produce antibodies•antigen-recognizing T cells → cell-mediated immune responses -activating macrophages-killing virus-infected cells•memmory cells - enhance response upon re-exposure11ADAPTIVE IMMUNE RESPONSE•Hypersensitivity reactions - inappropriately deployed immune reactions•anti-inflammatory and immunosuppressive drugs - used to counter these inappropriate immune reactions5Humoral and Cell-mediated ImmunityInnate ImmunityAdaptive Immunity12Chronic inflammation •Vascular system (flow and permeability changes, EC) •Migration of blood cells (infiltrate of lymphocytes & monocytes) •Chemical mediators (chemokines, cytokines, Igs, coagulation •Adaptive immune response •Time course is weeks to years •Tissue proliferation and destruction Inflammatory response (con’t)13Inflammatory Mediators/Signaling Molecules Arachidonic acid derivatives: (prostaglandins, thromboxanes & leukotrines) ! vasodilation, bloodflow, redness, edema, fever, vascular permeability, WBC migration, pain Bradykinin: vasoactive plasma peptides formed from kininogens; vasodilator, ! vascular permeability & pain Cytokines: IL-1 and TNF" released from tissue macrophages and see ! vascular permeability and ! adhesion molecule expression Chemokines: chemoattractants, IL-8, RANTES, MCP-1 Complement: lyse bacteria, ! EC permeability, opsonization Clotting mediators: (activated by platelets or collagen, Hageman/Factor XII) 14Thromboxanes: platelets aggregation & vasoconstriction Histamine: IgE mediated or complement


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UIC PCOL 425 - Anti-inflammatory agents

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