Patogenese Radang

Pathogenesis of InflammationDjumadi AchmadDept of Pathology Medical Faculty - Hasanuddin University

NM Almasri JUST

*InflammationDefinitionA dynamic vascular and cellular response of tissue to injury.Inflammation results in:- accumulation of leukocytes, and fluid in extravascular tissue.- systemic effects.

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Elimination of the cause of cell injuryElimination of the necrotic cellsPaves the way for repairMay lead to harmful resultsEffects of Inflammation

*Causes:Microbial infections: bacteria, viruses, fungi, parasites, mycoplasma.Immunologic: hypersensitivity (contact with some substances), autoimmune reactionsPhysical agents: trauma, heat, cold, ionizing radiation, etcChemical agents: acids, alkali, bacterial toxins, metals, etcForeign material: sutures, dirt, etcIschemic factor: ischemic necrosis,e.g acute MIInflammation

*InflammationThe participantsWhite blood cells and plateletsNeutrophils, monocytes, lymphocytes, eosinophils, basophilsPlasma proteinsCoagulation / fibrinolytic system, kinin system, complement systemEndothelial cells and smooth muscles of vesselsExtracellular matrix and stromal cellsMast cells, fibroblasts, macrophages & lymphocytesStructural fibrous proteins, adhesive glycoproteins, proteoglycans, basement membrane

*Components of Inflammation

*Acute InflammationEarly response of vascularized tissue to injuryAim of acute inflammation:Recruitment of neutrophils (1st 3 days), and monocytes (after 3 days) to clear the cause of injury and remove necrotic cells.Deliver plasma proteins: Antibodies, complement, others.

*The two events of acute inflammationVascular changesVasodilatationIncreased vascular permeabilityStasisCellular eventsEmigration of cells from microvesselsAccumulation at sites of injury

The process is orchestrated by release of chemical mediators

*Local Manifestations of Acute Inflammation

*The five classic signs of acute inflammationHeat(Calor)Redness(Rubor)Swelling(Tumor)Pain(Dolor)Loss of function

* Heat Redness Swelling Pain Loss Of Function.The five classic signs of acute inflammation

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*Vascular ChangesArteriolar dilatation Increased vascular permeability and stasis: Arteriolar vasodilatation hydrostatic pressure transudateLate phase: Leaky vessels loss of proteins exudateMargination of leukocytes

*The mechanisms of vascular leakage Endothelial cell contraction

*The mechanisms of vascular leakage Direct endothelial injury

*The mechanisms of vascular leakage Leukocyte-dependent endothelial injury

*The mechanisms of vascular leakage Increased transcytosis of protein

*The mechanisms of vascular leakage Leakage from newly formed blood vessels

*Edema in Inflammation

*Cellular EventsMargination, rolling and adhesion Transmigration between endothelial cellsMigration in the interstitium toward the site of stimulusPhagocytosis and degranulationRelease of leukocyte products

*Neutrophil Margination

*The Process of Extravasation of Leukocytes

*Adhesion between leukocytes and endothelial cellsWeak adhesion and rollingMediated by selectinsFirm adhesionIg superfamily molecules expressed on endothelial cells such as: ICAM-1 VCAM-1Integrins expressed on leukocytes:LFA-1 (CD11a/CD18)Mac-1 (CD11b/CD18)P150,95 (CD11c/CD18)VLA-4

*Upregulation of Selectins

*Cytokine Induction of Adhesion Molecules

*Chemotactics Increase Affinity of Integrins to Adhesion Molecules

*Endothelial and Leukocyte Adhesion Molecule InteractionsENDOTHELIUM molWBCrcptFUNCTIONP & E-selectinsSialyl-Lewis XRolling

GlyCAM-1, CD34L-selectinRolling

VCAM-1VLA-4Adhesion

ICAM-1CD11/CD18Adhesion, (LFA1, MAC1) PECAM-1CD31Transmigration

*Molecules Mediating Endothelial-Neutrophil Interaction

*Firm Adhesion via Integrin ICAM Interactions

*Transmigration of Neutrophils

*DiapedesisTransmigration of leukocytes between endothelial cells at the intercellular junctions

Facilitated by PECAM-1 (CD31)/PECAM-1 interaction

*The Process of Extravasation of Leukocytes

*Lobar Pneumonia

*ChemotaxisMigration of cells along a chemical gradientChemotactic factors:Soluble bacteial products, e.g. N-formyl-methionine terminiComplement system products, e.g. C5aLipooxygenase pathway of arachidonic acid metabolism, e.g. LTB4Cytokines, e.g. IL-8

*Effects of Chemotactic Factors on Leukocytes

*Effects of Chemotactic Factors on Endothelial Cells

*Effects of Chemotactic Factors on LeukocytesStimulate locomotionDegranulation of lysosomal enzymesProduction of AA metabolitesModulation of the numbers and affinity of leukocyte adhesion molecules

*PhagocytosisThe process of ingestion and digestion by cells of solid substances, e.g., other cells, bacteria, necrotic tissue or foreign materialSteps of phagocytosis:Recognition, attachment and binding to cellular receptors OpsoninsIgG, C3b, collectins-EngulfmentFusion of phagocytic vacuoles with lysosomesKilling or degradation of ingested material

*Phagocytosis

*Generation of Oxygen Metabolites2O2 + NADPH 2O2- + NADP+ + H+ O2- + 2H+ H2O2H2O2 +Cl- HOCl- The H2O2-MPO-halide is the most efficient bactericidal system in neutrophilsNADPH oxidaseDismutaseMyeloperoxidase

*How Do Leukocytes Kill Infectious Agents?Oxygen burst productsBactericidal permeability increasing proteinLysozymeMajor basic proteinDefensinsLactoferrin

*Genetic defects in leukocyte functionDiseaseLeukocyte adhesion deficiency 1

Leukocyte adhesion deficiency 2

Neutrophil-specific granule deficiency

CGD, X-linkedCGD, autosomal recessive

MPO deficiency

Chediak-Higashi diseaseDefectCD18 unit of integrin

Sialyl-Lewis X

Absent specific granules

Membrane component of NADPH oxidaseCytoplasmic component of NADPH oxidaseAbsent MPO-H2O2 system

Organelle trafficking

*Acquired defects in leukocyte functionChemotaxis defectsburns, diabetes, sepsis, etc.Adhesionhemodialysis, diabetesPhagocytosis and microbicidal activityleukemia, sepsis, diabetes, malnutrition, etc

*Chemical Mediators of InflammationWhat are their sources?Circulating plasma proteinsCoagulation / fibrinolytic factorsComplementKininsCell derivedFormed elements normally sequestered in granules:Vasoactive aminesNewly synthesized in response to stimulationPGs, LT, O2 species, NO, Cytokines, PAF

*Cellular Derived Mediators of Inflammation

*Systemic Mediators of Inflammation

*Histamine and SerotoninStored in granules in mast cells (histamine), and platelets (serotonin)Cause arteriolar dilatation and increases permeability (immediate phase reaction)Induce endothelial cell contraction in venulesBinds to H1 receptorsInactivated by histaminase

*Clotting / fibrinolytic systemFibrin clot at site of injury helps in containing the causeFibrin clot provides a framework for inflammatory cellsXa causes increased vascular permeability and leukocytes emigrationThrombin causes leukocytes adhesion, platelets aggregation, generation of fibrinopeptides, and is chemotacticFibrinopeptides are chemotactic & induce vasopermeability

*XIIa also activates the fibrinolytic pathway to prevent widespread thrombosis. Fibrin split products increase vascular permeabilityPlasmin cleaves C3 to form C3a, leading to dilatation and increased permeabilityPlasmin activates XIIa amplifying the entire process

Clotting / fibrinolytic system (continued)

*Thrombin as an Inflammatory MediatorBinds to protease-activated receptors (PARs) expressed on platelets, endothelial cells, sm. muscles leading to:P-selectin mobilizationExpression of integrin ligandsChemokine productionProstaglandin production by activating cyclooxygenase-2Production of PAFProduction of NO

*Kinin SystemLeads to formation of bradykinin from HMWKEffects of bradykininIncreased vascular permeabilityArteriolar dilatationBronchial smooth muscle contractionPainSort half-life (inactivated by kininases)

*XIIaXIIHMWK-ve surfaceprekallikerinkallikerinFibrinogenFibrinHMWKBradykininPlasminogenPlasminFibrin split productsC3C3aMultiple stepsInteraction between the four plasma mediator systems

*The Complement System in InflammationC3a and C5a (anaphylatoxins) increased vascular permeability, and cause mast cell to secrete histamineC5a activates lipoxygenase pathway of AAC5a activates leukocytes, increased integrins affinityC5a is chemotacticC3b and C3bi are opsoninsPlasmin and proteolytic enzymes split C3 and C5Membrane attack complex (C5-9) lyse bacterial membranes

*Complement Role in Inflammation

*Defects in the Complement SystemDeficiency of C3 susceptibility to infections.Deficiency of C2 and C4 susceptibility to SLE.Deficiency of late components low MAC Neisseria infections. inhibitors of C3 and C5 convertase ( DAF) hemolytic anemiaC1 inhibitor angioneurotic edema

*Generation of AA Metabolites

*Products of the cycloxygenase pathway of AA metabolismTXA2 VasoconstrictionSimulates platelets aggregationPGI2VasodilatationInhibits platelets aggregationPGD2, PGE2, PGF2aVasodilatationEdema formationPain (PGE2)

*5-HETE and LTB4ChemotacticLTC4, LTD4 and LTE4VasoconstrictionBronchospasmIncreased vascular permeabilityLipoxins (LXA4 & LXB4)VasodilatationInhibit neutrophil chemotaxis and adhesionStimulate monocyte adhesion

Products of the lipoxygenase pathway of AA metabolism

*Platelet-activating FactorGenerated from membranes phosphlipids by Phospolipase A2Aggregates and degranulates plateletsPotent vasodilator and bronchoconstrictorIncrease vascular permeabilityEffects on leukocytesIncrease adhesion to endothelial cellsChemotacticDegranulationOxygen burst

*CytokinesHormone-like polypeptides produced by cells, involved in cell to cell communicationPleiotropic effectsSecretion is transientRedundantEffects: autocrine, paracrine, endocrine

*Classes of cytokinesRegulators of lymphocyte functionIL-2 stimulates proliferationTGFb inhibits lymphocytes growthPrimary responders to injury (innate immunity)IL-1 & TNFActivators of cell mediated immunityINF-g & IL-12ChemotacticsIL-8Hematopoietic growth factorsIL-3 & GM-CSF

*TNF & IL-1Produced mainly by macrophagesSecretion stimulated by: bacterial products, immune complexes, endotoxins, physical injury, other cyotkines.Effects on endothelial cell, leukocytes, fibroblasts, and acute phase reactions

*Major Effects of IL-1 & TNF

*ChemokinesA group of related chemotactic polypeptides, all of which have 4 cysteine residuesRegulate adhesion, chemotaxis and activation of leukocytesImportant for proper targeting of leukocytes to infection sitesThe largest family consists of CC chemokines, so named because the first 2 of the 4 cysteine residues are adjacent to each other.Examples of CC chemokines:CCL2: Monocyte chemoattractant protein 1 (MCP-1)CCL3 & CCL4: Macrophage inflammatory protein 1 (MIP-1a & 1b)CCL5: RANTES CCL11: Eotaxin

*ChemokinesChemokines released in extravascular tissue move by transcytosis to the luminal surfaces of endothelial cellsBuildup of chemokine at the luminal surface of the endothelium occurs by chemokine immobilization mediated by interactions with cell surface proteoglycans such as heparan sulfate.The chemokines interact with the G-protein coupled receptors on the leukocyte cell surface, resulting in activation of integrins and firm attachment to the endothelium.

*Nitric OxideProduced from arginine by the effect of nitric oxide synthase (NOS)Role in inflammation:Vasodilator (smooth muscle relaxant)Antagonist of platelets adhesion, aggregation and stimulationReduces leukocytes adhesion and recruitmentMicrobicidal in activated macrophages

*Nitric Oxide

*Oxygen derived free radicalsAt low levelsIncrease:ChemokinesCytokinesAdhesion molecules

At high levelsEndothelial damage & thrombosisProtease activation & inhibition of antiproteasesDirect damage to other cellsProtective mechanisms against free radicals include: transferrin, ceruloplasmin, catalase, superoxide dismutase, and glutathione

*Lysosomal constituentsReleased in:After cell deathLeakage upon formation of phagocytic vacuolesFrustrated phagocytosis (fixed on flat surfaces)After phagocytosis of membranolytic substance, e.g. urateNeutral proteases effects:Elastases, collagenases, and cathepsinCleave C3 and C5 producing C3a & C5aGenerate bradykinin like peptidesMinimizing the damaging effects of proteases is accomplished by antiproteases:Alpha 2 macroglobulinAlpha 1 antitrypsin

*Morphologic Appearance of Acute InflammationCatarrhal Acute inflammation + mucous hypersecretion (e.g. common cold)SerousAbundant protein-poor fluid with low cellular content, e.g. skin blisters and body cavities Fibrinous: Accumulation of thick exudate rich in fibrin, may resolve by fibrinolysis or organize into thick fibrous tissue (e.g. acute pericarditis)

*Morphologic Appearance of Acute InflammationSuppurative (purulent): Pus: Creamy yellow or blood stained fluid consisting of neutrophils, microorganisms & tissue debris e.g. acute appendicitisAbscess: Focal localized collection of pusEmpyema: Collection of pus within a hollow organUlcers:Defect of the surface lining of an organ or tissueMostly GI tract or skin

*Subcutaneous Abscess

*Lung Abscess

*Fibrinous Pericarditis

*Burn Bister

*RESOLUTIONFIBROSISABSCESSFORMATIONREPAIR &ORGANIZATIONCHRONICINFLAMMATIONACUTEINFLAMMATIONUsual resultPyogenic organismExcessive destructionPersistenceOutcomesof Acute Inflammation

Chronic Inflammation

NM Almasri JUST

*Chronic InflammationInflammation of prolonged duration (weeks, months, or years) that starts either rapidly or slowly.Characterized by an equilibrium of:Persistent injurious agentInability of the host to overcome the injurious agent

*Chronic InflammationCharacteristics:Chronic inflammatory cell infiltrateLymphocytesPlasma cellsMacrophagesTissue destructionRepairNeovascularizationFibrosis

*Chronic InflammationUnder what circumstances, does it develop?Progression from acute inflammationTonsillitis, osteomyelitis, etc.Repeated exposure to toxic agentSilicosis, asbestosis, hyperlipidemia, etc.Viral infectionsPersistent microbial infectionsMycobacteria, Treponema, Fungi, etc.Autoimmune disordersRhumatoid arthritis, SLE, systemic lupus, etc.

*How do Macrophages Accumulate at Sites of Chronic Inflammation? Recruitment of monocytes from circulation by chemotactic factors:Chemokines, C5a, PDGF, TGFa, fibrinopeptides, fibronectin, collagen breakdown fragments.Proliferation of macrophages at foci of inflammationImmobilization of macrophages at sites of inflammation

*Role of Activated Macrophages in Chronic Inflammation

*Granuolmatous InflammationA distinctive form of chronic inflammation characterized by collections of epithelioid macrophagesGranuloma, in addition to epithelioid macrophages, may have one or more of the following: a surrounding rim lymphocytes & plasma cells a surrounding rim of fibroblasts & fibrosis giant cells central necrosis e.g. caseating granulomas in TB

*Histopathology of Granuloma

*Histopathology of Granuloma

*Caseating Granuloma

*AFB Stain in Caseating Granuloma

*Examples of Granulomatous Inflammation

BacterialMycobacterium tuberculosisMycobacterium LepraeTrepnema pallidumBartonella henslaeParasiticScistosomiasisFungalHistoplasma capsulatumBalsomycosisCryptococcus neoformansCoccidioides immitisInorganic metalsSilicosis, ByrelliosisForeign bodySuture, other prosthesis, keratinUnknown Sarcoidosis

*Morphologic Appearance of Chronic InflammationUlcerationUlcer: Local defect or loss of continuity in surface epitheliaChronic abscess cavityInduration & fibrosisThickening of the wall of a hollow viscusCaseous necrosis

*Ulcer

*Consequences of Defective InflammationSusceptibility to infectionsDefective innate immunityDelayed repairDelayed clearance of debris and necrotic tissueLack of stimuli for repair

*Allergic reactionsAutoimmune disordersAtherosclerosisIschemic heart diseaseConsequences of Excessive Inflammation

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