DegenerationACUTECELLULARSWELLING

Excessiveentryoffreefattyacidsintotheliver(starvation,corticosteroidtherapy).Enhancedfattyacidsynthesis.Decreasedfattyacidoxidation.Increasedesterificationoffattyacidtotriglycerides(alcohol).Decreasedapoproteinsynthesis(CCl4).Impairedlipoproteinsecretionfromtheliver(alcohol).FATTYCHANGEMorphologyoffattychangeSudanIII,OilredO,OsmicacidLiverHeartKidneyIntracellularhyalinechangesHyalinedegenerationofarteriolesHyalinedegenerationofconnectivetissueHyalinechanges(degeneration)Absorptionofproteincausinghyalinedropletsinproximalepithelialcellsinthekidney.Russelbodiesinplasmacells.Viralinclusionsinthecytoplasmorthenucleus.Massesofalteredintermediatefilaments(Mallorybodies).IntracellularhyalinechangesAheterogeneousgroupofpathogenicfibrillarproteinsaccumulatingintissuesandorgans.ExcesssynthesisResistancetocatabolismAMYLOIDOSISChemicalnatureofamyloidfibrilsTwomajorforms:AL(amyloidlightchainprotein)AA(amyloid-associatedprotein):

DerivedfromserumAA(12kd)synthesizedinliverandelevatedininflammatorystates.Minorformsofamyloidfibrils:Transthyretin(TTR):Amutantformofaserumproteininfamilialamyloidpolyneuropathy.AvariantofTTRinaging.Beta-2-microglobulin(thecomponentofclassIMHCmolecules)inlong-termhemidialysis.Minorformsofamyloidfibrils:

Beta-2-amyloidproteinformsthecoreofcerebralplaquesanddepositswithincerebralvesselwallsinAlzheimerdisease,derivingfromatransmembraneglycoproteinprecursor.Minorformsofamyloidfibrils:Transthyretin(TTR):Amutantformofaserumproteininfamilialamyloidpolyneuropathy.AvariantofTTRinaging.Beta-2-microglobulin(thecomponentofclassIMHCmolecules)inlong-termhemidialysis.Minorformsofamyloidfibrils:

Beta-2-amyloidproteinformsthecoreofcerebralplaquesanddepositswithincerebralvesselwallsinAlzheimerdisease,derivingfromatransmembraneglycoproteinprecursor.primary(B-celldyscrasia,AL)Secondaryorreactive(AA):Collagendiseases,bronchiectasis,chronicosteomyelitis.Hemodialysis-related:Beta-2-microglobulindeposition.Hereditary(AA)ClinicalformsofamyloidosisSystemicamyloidosis:Nodular(tumor-formingdeposits,B-celldyscrasia,AL)Endocrineamyloidosis(procalcitonin)Amyloidosisofaging:Heart,lung,pancreas,spleen,brain.Localizedamyloidosis

Exogenous:

CarbonTattooingEndogenous:LipofuscinMelaninHemosiderinBilirubinPigmentationDystrophiccalcificationMetastaticcalcificationPathologiccalcificationNecrotictissuesAtheromaDamagedheartvalvesDystrophiccalcificationFig2-13IncreasedsecretionofparathyroidhormoneDestructionofbonetissueVitaminD-relateddisorders:SarcoidosisRenalfailureMetastaticcalcificationHypercalcimiaMetastaticcalcificationAffectingInterstitialtissueofgastricmucosaKidneysLungsPulmonaryveinsSystemicarteriesHyperemia:

ArterialhyperemiaVenoushyperemia

ChapterFour

HemodynamicDisordersArterialhyperemiaInflammatoryCollateralPost-ischemicVenoushyperemiaSystemiccongestionHeartfailuresLocalcongestion1.Externalpressure2.Thrombosis3.Venousvalves4.CollateralEdemaHemorrhageHeartfailurecellsBrownindurationPulmonarycongestionLivercongestionAtrophyFattychangeNutmegliverCentrilobularnecrosiscardiaccirrhosisINFARCTION(INFARCT)

ThrombosisEmbolismVesospasmExpansionofatheromaExtrinsiccompressionTwistingofthevesselsEtiologyINFARCTIONShape:Wedge-shapedSegmentalIrregularNatureofnecrosisTypes:RedandwhiteinfarctsMorphologyofinfarctVenousocclusionsLoosetissuesTissueswithdualcirculationsTissuespreviouslycongestedBloodflowreestablishedRedinfarct

CELLDEATHSwelling,denaturationandcoagulationofproteinsBreakdownofcellularorganellesCellrupture

Commontypeofnecrosisafterexogenousstimuli.NECROSISThesumofthemorphologicchangesthatfollowcelldeathinlivingtissueandorgan:Denaturationofproteins.Enzymaticdigestionoforganellesandcytosol.Enzymaticdigestionbylysosomalenzymesofthedeadcellsthemselves.AUTOLYSISHETEROLYSISDigestionbylysosomalenzymesofimmigrantleukocytes.ThreepatternofnuclearchangesKaryolysis(DNaseactivity)Pyknosis(DNAcondensation)Karyorrhexis(fragmentationofpyknoticnucleus)MorphologicappearanceofnecrosisIncreasedeosinophilia:LossofRNAinthecytoplasmIncreasedbindingofeosintodenaturedcytoplasmic

proteinMoreglassyhomogeneousappearanceLossofglycogenparticlesVacuolatedandmoth-eatencytoplasmCalcificationofnecroticcellsTYPESOFCELLDEATH

necrosis

Coagulationnecrosis

Caseousnecrosis

Gangrene

Liquefactionnecrosis(fatnecrosis)FibrinoidnecrosisApoptosisCoagulationnecrosisDenaturesofbothstructuralandenzymaticproteinsbyinjuryorthesubsequentincreasingintracellularacidosis.CaseousnecrosisAsubtypeofcoagulationnecrosisWhiteandcheesyTuberculosisCompletelyobliteratedtissuearchitectureGangreneAsubtypeofcoagulationnecrosisDrygangreneWetgangreneGasgangreneLiquefactivenecrosisBacterialorfungalinfectionsCentralnervoussystemAmebiasisFatnecrosisTraumaticActivatedpancreaticlipasesFibrinoiddegenerationDeeplyeosinophilicCollagendiseasesNecroticvasculitisMalignanthypertensionAPOPTOSIS(Programmedcelldeath)

Programmeddestructionofcellsduringembryogenesis.Hormonedependentinvolutionoftissuesintheadult.Celldeletioninproliferatingcellpopula-tions(intestinalcryptepithelium),tumors,andlymphoidorgans.Pathologicatrophyinparenchymalorgansafterductobstruction.CelldeathbycytotoxicTcells.Cellinjuryincertainviraldiseases.Celldeathproducedbyavarietyofinjuriousstimuligiveninlowdoses(e.g.mildthermalinjury).MORPHOLOGICALFEATURESOFAPOPTOSISCellshrinkageChromatincondensationandfragmentation.Formationofcytoplasmicblebsandapoptoticbodies.Phagocytosisofapoptoticbodiesbyadjacenthealthycellsormacrophages.Lackofinflammation.

Necrosis

ApoptosisStimuliHypoxiaPhysicalToxinsPathologicalHistology

CellswellingSinglecellCoagulationNChromatinDisruptionofcondensationorganellesApoptoticbodiesDNA

RandomInternucleosomalbreakdown

Diffuse

Necrosis

ApoptosisMechanismATPdepletionGeneactivationMembraneEndonucleaseinjuryFreeradicalsTissueInflammationNoinflammation

reaction

PhagocytosisofapoptoticbodiesFig1-18Biochemicalfeaturesofapoptosis1.PROTEINCLEAVAGE:

Caspases(cysteineprotease)NuclearscaffoldCytoskeletalprotein2.PROTEINCROSS-LINKING:

TransglutaminaseCytoplasmicprotein

shrunkenshalls

apoptoticbodiesBiochemicalfeaturesofapoptosis3.DNAbreakdown:50-300kbpiecesCa2+,Mg2+dependentendonucleasesDNAoligonucleosomesDNAladders(alsoseeninnecrosis)4.PHAGOCYTICRECOGNITION

Receptorsonmacrophagesforthesurfacecomponents(phosphatidylserine,thrombospondin)onapoptoticbodies.Fig1-19Apoptosis-associatedgenesbcl-2,c-myc,p53Fig1-20AbsorptionDischarge:ErosionUlcerSinusFistulaCavitationOrganizationEncapsulationCalcificationFatesofnecrosisRegeneration:CompletelyregenerationFibrousrepairChapterThreeRepairSectionALabilecellsStablecellsPermanentcellsRegenerationcapacity1.Cell-cellinteractionConditionedmediumContactinhibition2.ExtracellularmatrixLaminin:

Epithelia

FibroblastsFibronectin:

Epithelia

Fibroblasts3.GrowthfactorsFactorsinfluencingregenerationGROWTHFACTORSEGF,TGF-A,PDGF,aFGF,bFGF,IGF-1,IGF-2,VEGF,HGF,MG-CSF,M-CSF,G-CSF,ERYTHROPOITIN,ILs,TNF,IFN,NGF.SectionB

FibrousRepair

Granulationtissues:NewlyformedcapillariesFibroblastsInflammatorycellsGranulationtissuesFibrousrepairOrganizationWoundhealingFig4-14Fig4-15HealingbyfirstintentionHealingbysecondintentionHealingunderscabWoundhealingFig4-18Fig4-19Systemicfactorsinfluencingwoundhealing:

NutritionMetabolicstatusCirculatorystatusHormonesInfectionMechanicalfactorsForeignbodiesSize,locationandtypesofwoundLocalfactorsinfluencingwoundhealing:LiquefactivenecrosisBacterialorfungalinfectionsCentralnervoussystemAmebiasisFatnecrosisTraumaticActivatedpancreaticlipasesEmbolismEmbolusEmboli

EmbolusfromleftheartcavityorarterialsystemEmbolusfromrightheartcavityorvenoussystemEmbolusfromportalveinsParadoxicalembolismRetrogradeethrombusMotionalpathwayofembolus:Fig5-16THROMBOEMBOLISMInstantaneousdeath(>60%).Cardiovascularcollapse.Hemodynamiccompromise.Pulmonary1.Largeemboli(5%):2.Smallemboli(60-80%):Clinicalsilentinpatientswithoutcardiovascularfailure.Infarctionsinthosewithcompromisedpulmonarycirculation(10-15%).3.Betweentheextremesoflargeandsmallemboli(10-15%):Pulmonaryhemorrhage.4.Multipleovertorcovertsmallemboli:Pulmonaryhypertensionandvascularsclerosis.SystemicembolismI.80-85%fromheart,secondarytomyocardialinfarction.II.5-10%fromauricularthrombiassociatedwithrheumatic heartdiseaseandatrialfibrillation.III.5%fromthedilatedcardiacchamberofmyocarditis/ cardiomyopathy.VI.Lesscommonsources:Debrisfromulcerativeatheromata, orthrombiinaneurysms,infectiousendocarditis, prostheticvalves,paradoxicalemboli.V.Unknown.Etiology:FracturesoflongbonesSofttissuetraumaBurnsFatembolism90%ofindividualswithsevereskeletalinjuries10%withclinicalfindingsPulmonaryinsufficiencyNeurologicsymptoms9-20gFatembolismFig5-17Etiology:IntravenoustherapeuticproceduresObstetricproceduresChestwallinjuryDecompressionsickness(nitrogen)AirembolismClinicaleffect:>100ccBends,focalischemiaAtelectasisandemphysema(choke)Caissondisease(amorechronicform):Multiplefociofischemicnecrosisinskeletalsystem(femurs,tibia,humor)AirembolismAMNIOTICFLUIDINFUSIONIncidence:1/50000deliveriesMortalityrate:80%Clinicalonset:Suddenseveredyspnea,cyanosis,hypotensiveshock,seisuresandcoma.AMNIOTICFLUIDINFUSIONEmbolizationofthepulmonarymicrocirculationoftheparticulatedebrisinamnioticfluid.Releaseofvasoconstrictoragents,e.g.,PGreducingpulmonarybloodflow.IntercurrenceofDIC.Cellularadaptation:AtrophyHypertrophyHyperplasiaMetaplasiaChapterTwoTissueinjury

CELLULARADAPTATIONExcessivephysiologicstresses.Somepathologicstimuli.Anew,butalteredstatepreservingtheviabilityofthecell.ATROPHYDecreaseinmassofthecellHYPERTROPHYIncreaseinmassofthecellATROPHYDecreasedworkload.Lossofinnervation.Diminishedbloodsupply.Inadequatenutrition.Lossofendocrinestimulation.AgingMorphologyofatrophyBrownatrophyReductioninthenumberofcellorganelles.Increaseinthenumberofautophagicvacuoles.Lipofuscingranules(Brownatrophy)Fig2-5HYPERTROPHYIncreasedfunctionaldemand.Specifichormonalstimulation.Fig2-6HYPERPLASIAThemythofPrometheus.HYPERPLASIAPhysiologichyperplasia:HormonalhyperplasiaCompensatoryhyperplasiaPathologichyperplasia:Excessivehormonalstimulation.EffectsoflocallyproducedGFsontargetcells.

Fig2-1PARTIALHEPATECTOMYPrimingProliferationGroethlnhibitionGROWTHFACTORSANDCYTOKINESHGFTGF-

EGFTNF-

IL-6OthersADJUVANTSNorepinephrineInsulinGlucagonThyroidhormoneGROWTHINHIBITORSTGF-

OthersGrowthfactorsAdjuvanisMatrixdegradationMetaplasiaOneadultcelltypeisreplacedbyanother.Geneticreprogrammingofstemcells.Epithelialandmesenchymalmetaplasia.Squamousmetaplasia

BronchialepitheliaEpitheliainbileductCervicalepitheliaIntestinalmetaplasiaofgastricepitheliaBonemetaplasia.ThrombosisThrombusThrombi

ANTITHROMBOTICPROPERTIESInhibitionofplateletaggregation:PGI2,NO,ADPaseAnticoagulant-bindingandinhibitionofthrombin:AntithrombinIIIaccelerationbyheparin-likemolecules,thrombomodulinactivationofproteinC/S,

2-macroglobulin.Fibrinlysis:Tissueplasminogenactivator(tPA)PROTHROMBOTICPROPERTIESSimulationofplateletaggregation(adhesion):vonWillebrandfactor,platelet-activatingfactor.Procoagulationfactors:Tissuefactor,bindingfactorsIXaandXa,FactorV.Inhibitionoffibrinolysis:t-PAinhibitor.Fig5-5Fig5-6THREEINFLUENCESOFTHROMBOSISEndot