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Inflammation
This document discusses inflammation and its triggers, objectives, and results. It describes the cardinal signs of inflammation as redness, swelling, heat, pain, and loss of function. It differentiates between acute and chronic inflammation and discusses the cells, mediators, and systemic effects involved in each. Key aspects of the inflammatory response like increased vascular permeability, leukocyte recruitment, recognition of pathogens, and termination signals are explained.
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Inflammation
- 1.
- 2. Tissue Response toInjury
- 4. InflammationTriggers:Infectious organismsTraumaObjectives: Removethe triggerRemove any dead tissue End Result: Resolves when harmful stimulus is eliminatedAs Inflammation ends, Repair starts
- 5. InflammationProtective innatureRemoves harmful agents Enables tissue to healMay itself be harmfulToo much Misdirected
- 6. The Cardinal Signsof InflammationRubor (redness)Tumor (swelling)Calor (heat)Dolor (pain)Functio Laesa (loss of function)
- 7. The Cardinal Signsof Inflammation
- 8. InflammationAcuteRapid onsetShort durationNeutrophilsExudationof fluid and plasma proteinsInflammation followed by RepairChronicSlow onset; may follow acuteLonger durationLymphocytes and MacrophagesProliferation of blood vesselsSimultaneous Inflammation and Repair
- 9. Acute Inflammation -TriggersInfections - Organisms and their toxinsTissue Necrosis - Ischemia, Chemical injuryForeign Bodies - Traumatic tissue injury Immune Reactions - Hypersensitivity
- 10. Acute InflammationChanges inVascular Caliber and FlowIncreased Vascular PermeabilityEmigration of Leukocytes
- 11. Acute InflammationBlood vesselsIncreasedcaliberIncreased permeabilityLeukocytesRecruitmentChemotaxisPhagocytosis
- 12. Vasodilation Initial transientvasoconstriction of arteriolesHistamine and NO act on vascular smooth muscleVasodilation follows after a few secondsIncreased blood flow in the areaOpening of new capillary beds
- 13. Increased Vascular PermeabilityRetraction of endothelial cellsHistamine, Bradykinin, NO, Substance PEndothelial injuryDirect damage from burnsInfectious organismsNeutrophils
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- 16. Leukocyte RecruitmentMargination: Slowblood flowWhite cells redistribute along periphery of lumen
- 17. Leukocyte RecruitmentRolling: Mediatedby Selectins and their LigandsHistamine and Thrombin: Induce P-Selectin expression TNF and IL-1: Induce E-selectin and L-Selectin ligandLeukocytes: Express L-selectin and Ligand for E and P Selectins
- 18. Leukocyte RecruitmentActivation: Chemokines(IL-8, PAF) activate leukocytesIntegrins (VLA-4, LFA-1) converted to high affinity states
- 19. Leukocyte RecruitmentAdhesion: Mediatedby Integrins and their LigandsTNF, IL-1: Induce endothelial expression of ligands for Integrins VLA-4: VCAM-1LFA-1: ICAM-1
- 20. Leukocyte RecruitmentDiapedesis: Chemokinesstimulate adherant leukocytes to migrate through inter-endothelial spacesPECAM-1 (CD31)
- 21.
- 22. ChemotaxisMovement along achemical gradientLeukocytes adhere to surrounding tissue cellsExtend flopodia in the direction of movementChemotactic agents: Exogenous: Bacterial productsEndogenous: IL-8C5aLTB4
- 23.
- 24. RecognitionToll-like Receptors forMicrobial ProductsBind bacterial lipopolysaccharides, proteoglycans and lipids, and double stranded RNA (viral product) Stimulate production of mediators and microbicidal substances G Protein-coupled ReceptorsBind bacterial peptides containing N-formylmethionyl residuesBind chemokines, complement proteins (C5a) and PAFConvert Integrin to high affinity stateStimulate chemotaxis
- 25. RecognitionReceptors for OpsoninsIgGspecific for the particleComplement proteins (C3)Facilitate phagocytosis of microbesReceptors for CytokinesIFN-ɣCause production of microbicidal substances
- 26.
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- 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.
- 33. Defects in LeukocyteFunction
- 36. Mediators of InflammationOriginCellsor Plasma ProteinsPreformed or SynthesizedActivationIn response to various triggersAmplificationOne mediator can stimulate release of othersActionsDifferent effects on different cellsDeactivationInactivated / Decay / Inhibited quickly
- 37. Mediators of InflammationCellDerivedVasoactive AminesAA MetabolitesPAFROSNOCytokinesChemikinesLysosomal EnzymesNeuropeptidesPlasma ProteinsComplement SystemCoagulation PathwayKinin System
- 38. Vasoactive Amines -HistaminePreformed in Mast cells and BasophilsTriggersPhysical injuryAb’s binding to Mast cellsComplement Proteins (C3a, C5a)Effects: Dilation of arteriolesIncreased permeability of venules (interendothelial gaps)
- 39. Vasoactive Amines -SerotininPreformed in plateletsTrigger for release: Platelet aggregation after contact with collagenEffect:Increased vascular permeability
- 40. Arachidonic Acid MetabolitesArachidonicAcid: 20-C Polyunsaturated Fatty AcidNormally esterified in membrane phospholipidsPhysical/Chemical injury activates Phospholipase A2 Releases AA from the membrane Metabolism through two pathwaysCyclooxygenase PathwayLipoxygenase PathwayAA-derived mediators act through G-Protein coupled receptors
- 42. Platelet Activating FactorOriginallydescribed as a factor that causes platelet aggregationReleased by: Platelets, Endothelial cells, Basophils, Mast CellsEffects: VasodilationIncreased vascular permeabilityIncreased leukocyte ashesionChemotaxisOxidative burst
- 43. Reactive Oxygen SpeciesOxygenderived free radicals may be released extra-cellularlyProduction depends on Phagocyte OxidaseEffects: Endothelial damage, leading to Increased vascular permeabilityInjury to interstitial cellsInactivation of Anti-ProteasesAnti-oxidants: Superoxide dismutaseCatalaseCeruloplasminTransferrin
- 44.
- 45. Cytokines - TNFand IL-1
- 46. ChemokinesSmall (8-10kD) proteinsDiverseactions depending on cell typeAct as chemoattractants40 different chemokines in 4 groups20 different receptorsCXCR-4 and CCR-5 receptors are site of entry of HIV
- 47. Neuropeptides - SubstancePTransmission of pain signalsRegulation of blood pressureIncreased vascular permeability
- 48.
- 49. Plasma ProteinsComplement ProteinsCoagulationFactorsKinin Proteins
- 50. Plasma Proteins -Complement System
- 51. Plasma Proteins -Complement System
- 53. Coagulation and KininSystemsExposed Collagen activates Factor XIIExtrinsic pathway startsThrombin binds PAR1 Receptors Mobilization of P selectin Increased recruitment of leukocytesInduction of COX-2
- 54. Coagulation and KininSystemsKallikerinActivates Factor XIIChemotacticBradykininActivates Factor XIIIncreased vascular permeabilityVasodilationPlasminActivates Factor XIILysis of fibrin clotsCleaves C3 to produce C3 fragments
- 56. Chronic InflammationInflammation fora prolonged period (weeks-months)Onset After Acute InflammationWhen injurious agent is not removed promptlyMore and more inflammatory cells are recruited to site of injuryInsideous OnsetLow intensity injury for long period of timeInflammatory response is not overwhelmingInjury and inflammation persist
- 57. Chronic Inflammation -CausesPersistent infection MTBVirusesFungiParasitesImmune mediatedAutoimmune diseases (Rheumatoid arthritis)Allergic diseases (Broncial asthma)Prolonged exposure Silicosis (Pulmonary fibrosis)
- 58. Chronic Inflammation -FeaturesInflammatory infiltrateMacrophagesLymphocytesPlasma CellsTissue destructionPersistent injuryInflammatory cells and MediatorsRepairAngiogenesisFibrosis
- 61. Chronic Inflammation -CellsMacrophagesLymphocytesPlasma CellsEosinophilsMast CellsNeutrophils!
- 62.
- 65. Chronic Inflammation -CellsPlasma CellsDevelop from activated B lymphocytesProduce Ab’s against the target AgEosinophilsIgE mediated immune reactions (Allergy)Parasitic infectionsRecruited by eotaxinGranules contain Major Basic Protein (Toxic to parasites)
- 67. Chronic Inflammation -CellsMast CellsBind Fc portion of IgE AbDegranulation when cell bound IgE Ab binds AgRelease Histamine, SerotininAllergic reactions to food, drugsNeutrophilsPersistent microbes (Osteomyelitis)Repeated injury (Lung damage due to smoking)
- 68. Granulomatous InflammationDistinctive typeof chronic inflammationAttempt to contain an offending agent that is difficult to eradicateStrong activation of T cells and MacrophagesExamples: TB - Fungal Infection - Syphilis
- 69. Leprosy - Sarcoidosis - Crohn’sGranulomaFocusof chronic inflammationMay have central necrosisAggregation of macrophages that are transformed into epithelioid cellsEpithelioid cells fuse to form Giant CellsSurrounded by lymphocytes and plasma cells
- 70. Foreign Body GranulomaInertforeign bodiesTalcSuturesForeign Body-type Giant CellsHaphazardly arranged nuclei
- 71.
- 72. Immune Granuloma -Sarcoidosis
- 73. Systemic Effects ofInflammationFeverInduced by pyrogensLeukocytes release IL-1, TNF upon activationIL-1, TNF induce Cyclooxygenase; PG producedPGE2 stimulates production of cAMP in hypothalamusTemperature set point is reset to a higher level
- 74. Systemic Effects ofInflammationAcute Phase Proteins upregulatedC Reactive Protein and Serum Amyloid A ProteinBind microbial cell walls; act as opsoninsSerum Amyloid A ProteinFaciltates transport of HDL to macrophagesFibrinogen Binds red cells and causes rouleaux formation Leads to increased ESR
- 75. Systemic Effects ofInflammationLeukocytosis Leukemoid reaction with Left ShiftLymphocytosisLeukopeniaEosinophilia
- 76. The Cardinal Signsof Inflammation
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