1Inflammation - The body’s natural response to injuryCharacteristics:Dilation (increase in diameter) & fenestration (increase in permeability) of the capillariesEdema (swelling, redness)Local rise in temperaturePain, sensitivity to painInflux of leukocytes, esp. Polymorphonuclear leukocytes (PMNs), and macrophagesIncreased (~tenfold) drainage into lymphatic systemPMN infiltration into damaged tissueBLOOD CELLSType Function Cells/ml bloodRed Blood CellsErythrocytes transport O2, CO25 X 1012White Blood Cells (leukocytes)GranulocytesPMNs/neutrophils phagocytose bacteria 5 X 109Eosinophils allergic response 2 X 108Basophils release histamine/serotonin 4 X 107Monocytes become macrophages 4 X 108LymphocytesB-cells make antibodies 2 X 109T-cells cell-mediated immunity 1 X 109Platelets blood clotting 3 X 10112Effectors of InflammationInterleukins - signaling peptidesIL-1: released by macrophages & other cells after injuryActivates phospholipase -> prostaglandin synthesisSynthesis of IL-8 & ELAMIL-8: chemotactic factor - attracts PMNs, PMN adhesionProstaglandins: from arachidonic acid -vasodilationSensitizes nerve endings to painLeukotrienes: chemotactic factors from arachidonic acidHistamines: -> permeability of capillary entothelial cells3PMN infiltration into damaged tissueIL-1 & Histamines -> endothelial cellsIL-8 & leukotrienes -> PMNsInjuryIL1syn.ELAMsyn.IL8syn.PhospholipaseAcitvityHistamineReleaseLeukotrienesyn.Prostaglandinsyn.AttractPMNsPMN Adhesion toEndothelial CellsFenestrationDilationEdemaPMNInfiltrationOverview of the Inflammatory ResponseIL = interleukinsyn. = synthesisELAM = entothelial leukocyte adhesion moleculePMNs = polymorphonuclear leukocytes4Linkage of inflammation to other systemsComplement system - activated by antibody-antigen complexes, activation of proteases that can damage normal tissueClotting/fibrinolytic system - intimately linked to late stages of inflammation as part of the healing processResolution of inflammationThe normal scenario: inflammation as part of healingPMNs phagocytose foreign organism or agentElimination through lymphatic systemProduction of inflammatory effectors ceasesInflammation, PMN infiltration & edema subsidesChronic inflammation:Inflammatory stimulus not removed by PMNsPMNs continue to release degradative enzymesDamage to normal tissue, more inflammationThis chronic, maladaptive inflammation must be controlled pharmacologicallyInflammatory disease: rheumatoid arthritisA disease of inflammation and autoimmunityAffects the joints - localized to synovial membraneInitiating event - unknown - genetic predispositionRheumatoid factor An IgM antibody against IgGPresent in most rheumatoid patientsProduced by B-cells in synovial fluid5Rheumatoid arthritis - ProgressionRheumatoid factor complexes trigger complement-> tissue damageAttract PMNs & macrophagesPannus: PMNs + macrophages + fibroblasts form scarlike tissue that accumulates in the jointIL-1 and TNFα produced by pannus -> proliferation and bone resorption by osteoclasts (from macrophages)6RA: treatment with NSAIDs(nonsteriodal antiinflammatory drugs)NSAIDs inhibit cyclooxygenase (COX) -> block prostaglandin synthesis -> reduce sensitivity to painNo effect on radiographic progression of joint disease1st generation: aspirinCovalent COX modification (acetylation) -> irreversible inhibitionGI side effects - increased acidity, decreases mucous2nd generation: propionic acid derivatives, e.g. IbuprofenReversible binding & COX inhibitionReduced GI effects NSAIDsInjuryIL1syn.ELAMsyn.IL8syn.PhospholipaseAcitvityHistamineReleaseLeukotrienesyn.Prostaglandinsyn.AttractPMNsPMN Adhesion toEndothelial CellsFenestrationDilationEdemaPMNInfiltrationOverview of the Inflammatory ResponseIL = interleukinsyn. = synthesisELAM = entothelial leukocyte adhesion moleculePMNs = polymorphonuclear leukocytes7RA: treatment with NSAIDs(nonsteriodal antiinflammatory drugs)3rd generation: longer-acting COX inhibitorse.g., nabumetone (Relafen), naproxen (Alleve)half-life ~1-2 days -> less frequent dosage4th generation: selective COX-2 inhibitorscelecoxib (Celebrex), rofecoxib (Vioxx)COX-1: basal activity in all normal tissuesCOX-2: very low basal activity, greatly increased in inflamed tissueMinimal GI side effectsOccasional hepatotoxicity - monitor functionRA: treatment with DMARDs(disease-modifying antirheumatic drugs)DMARDs can actually arrest or slow RA progression(i.e., joint erosion as seen on X-rays)More toxic than NSAIDS1st generation: gold compounds, e.g., aurothioglucoseAccumulate in monocytes & macrophagesInterfere with migration and phagocytosisToxicity: colitis, immune dysfunctionsWeekly IM injections2nd generation: cytotoxic B/T cell inhibitorse.g., methotrexate, leflunomideBlock synthesis of pyrimidines (used to make DNA)Prevent B and T cell proliferation -> rheumatoidfactor not producedRA: treatment with DMARDs(disease-modifying antirheumatic drugs)8IL-1 + TNFα (from macrophages) stimulate osteoclastsOsteoclasts resorb bone -> joint destructionEtanercept (Enbrel) - soluble form of TNFα receptorInfliximab - monoclonal antibody to TNFαEither drug binds TNFα, prevents it from binding to receptors on osteoclasts -> bond resorption preventedToxicities - Hepatotoxicity, opportunistic infectionsfrom inhibition of immune function, esp. TuberculosisWork best if given immediately upon diagnosisProteins: need to be given by injectionCost: ~$10,000/yrRA: treatment with DMARDs3rd generation: TNFα antagonists (“biologicals”)TNFα activates TNF receptor(boneresorption)cell membraneoutsideinsideEnbrel is a decoy that competes with the TNF receptor for binding TNFα9Changing concepts in RA treatmentOld paradigm: Treat conservatively with NSAIDs as long as these are effective; switch to DMARDs only when necessary in later more severe stages of the diseaseNew paradigm: Treat aggressively with DMARDs as soon as RA diagnosed - early “window of opportunity”Mechanism: block transcription of IL-1 in response to injury and of IL-8 in response to IL-1Dramatic, rapid suppression of inflammationSerious toxicities -> only given as last resort when other treatments fail or as a temporary measure while DMARDs take effectSystemic administration - suppresses immune response overall; can suppress symptoms of serious illnessIntra-articular injection - promotes cartilage degeneration if given repeatedlyRA: treatment with