病理學(xué)教學(xué)課件：細胞的適應(yīng)、變性與死亡

細胞的適應(yīng)、損傷與死亡Cellularadaptation,cellinjury,andcelldeath

AdaptationCellinjuryAlteredphysiologicstimuliInjuriousstimuliMetabolicstimuliDegenerationCellularResponsesconfinedtoaverynarrowrangeoffunctionandstructurehandlenormalphysiologicdemands,maintainingasteadystate-“homeostasis”NormalCellStimuliCelldeathToomuchoverloadedTissuerenewalandrepairInabilitytoadapt2CellularAdaptationDefinitionPhysiologicstressesorpathologicstimuliAnew,butalteredstatepreservingtheviabilityofthecell→decreased→increased→increasedBy→transformationSizeNumberTypeAtrophyHypertrophyHyperplasiaMetaplasia﹜3ATROPHYShrinkageinthesizeofthecellbylossofcellsubstanceAdaptationCellatrophy→tissueatrophy→organatrophyPhysiologicvs.PathologicDiminishedfunction,butachieveanewequilibrium-proteinsynthesisvs.degradationCommoncausesDecreasedworkloadLossofinnervationDiminishedbloodsupplyInadequatenutritionAging（senileatrophy）LossofendocrinestimulationPressure4Fig2-5NormalThymusAtrophicThymusPhysiologicAtrophy5NormalStriatedMuscleAtrophicStriatedMuscleAtrophicSkeletalMuscleAtrophyofDisuseorInnervationAtrophyThinnerstriatedmusclefibersbylosingsarcoplasmLooserarrangement,replacedwithadiposetissue6Smoothandconvexoutersurface,finegranularitySymmetricallyreducedinsizeanddecreasedinweightAlternatingareasofatrophyandhypertrophyHypertensiveheartdiseaseandlatestageofchronicglomerulonephretisGranularAtrophyofkidney7Aging(Senile)AtrophyorIschemicAtrophyBrownatrophyDecreasedsizeandthinnerwallsProminenttortuouscoronaryarteriesonthepercardialsurfaceNormalHeartBrownAtrophyofHeartNormalHeartBrownAtrophyofHeart8PressureAtrophyofBrainPressureAtrophyofkidney

-HydronephrosisCompressedatrophyofkidneyAtrophy

canbemanifestedasanincreasedorgansizeDilatedrenalpelvis,compressedatrophyofrenalparenchyma9MorphologyofAtrophyBrownatrophyresidualbodiespresentinsufficientamountsabrowndiscolorationtothetissueLipofuscingranulesSomecelldebriswithintheautophagicvacuolemayresistdigestionPersistasmembrane-boundresidualbodiesRemainasasarcophagusinthecytoplasmDecreasednumberofcellorganellesIncreasedautophagicvacuolesmembrane-boundvacuolescontainfragmentsofcellcomponentshydrolyticcontentsdischargedbylysosomesdestinedfordestructionLipofuscinGranulesBrownAtrophyofHeart10ATROPHYAdaptationHYPERTROPHY

IncreasedcellsizebysynthesizingmorecomponentsCellhypertrophy→organhypertrophyPhysiologicvs.pathologicSpecifichormonalstimulationIncreasedfunctionaldemands11Occurconcomitantlywithhyperplasiaornot?Cellscapableofdivision→hypertrophy+hyperplasiaNondividingcells→hypertrophyonlyNormaluterusHyertrophicUterusNormalUterusHyertrophicUterusNormalHeartHyertrophicHeartNormalheartHyertrophicheart12ATROPHYAdaptationHYPERTROPHY

HYPERPLASIA

IncreasednumberofcellsinanorganortissuePhysiologicHormonalhyperplasia&Compensatoryhyperplasia(themythofPrometheus)PathologicExcessivehormone&locallyproducedGFsAbnormalbutremainscontrolled,willregressafterstimulationiseliminatedHowever,afertilesoilforcancerousproliferation13ProstateHyperplasia14ProstateHyperplasiaATROPHY,HYPERTROPHY

&HYPERPLASIAAdaptationMETAPLASIA

Oneadult

celltypeisreplacedbyanotheradultcelltypeGeneticreprogrammingofstemcellsinducedbycytokines,GFsandextracellularmatrixcomponentsAnadaptivesubstitution:sensitivetostress（eg.fragilecolumnar→betterabletowithstandtheadverseenvironment(ruggedsquamous)Two-edgedsword,malignanttransformationEpithelialvs.mesenchymalmetaplasia15SquamousMetaplasiaofBronchialEpitheliaAB/PASStainingShowsGobletCellsIntestinalMetaplasiaofGastricMucosaSqamousMetaplasiaofCervicalMucosa17DegenerationDefinitionMetabolicderangementAccumulationofabnormalamountsofvarioussubstancesFeaturesTransientlyorpermanentlyHarmlessorseverelytoxicLocatedincytoplasmornucleus，intracelluarorextracelluarProducedbyitselformerelystoresproductscomingfromelsewhere18CausesAnormalendogenoussubstanceis

produced

atanormalorincreasedrate,buttherateofmetabolismisinadequatetoremoveit.FattydegenerationinhepatocytesHyalinedegenerationinrenaltubularcellsAnormalorabnormalendogenous

substanceaccumulates,becauseofgeneticoracquireddefectsinthemetabolism,packaging,transport,or

secretion

ofthesubstance.StoragediseaseAnabnormalexogenoussubstanceis

depositedandaccumulates.Carbonortattooing19waterDegenerationNormalcellularconstituentAbnormalsubstancePigmentslipidsproteinscarbohydrateCellularswellingFattychangeCholesteralandcholesteralestersHyalinechangeAmyloidosisexogenousendogenousCarbon&tattooinglipofuscinMelaninHemosiderinBilirubinCategorizedbystockpiledsubstance20CellularSwelling（HydropicChange）Lossoffunctionofplasmamembraneenergy-dependentionpumpsIncapableofmaintainingionicandfluidhomeostasisFirstmanifestationofcellinjury21MorphologyWholeorgan:pallor,turgorandincreasedweightEnlarged,roundandswollencells.Paleandclearcytoplasm.clearvacuoles.SwellingandrarefactionofMtPinched－offsegmentsofERHydropicdegenerationinhepatocyte22FattyChange(Steatosis)AbnormalaccumulationoftriglyceridswithinparenchymalcellsCausesToxins(eg.alcoholabuse),proteinmalnutrition,diabetesmellitus,obesityandanoxiaOfteninliver(majororganinvolvedinfatmetabolism),alsooccursinheart,muscleandkidney23SignificanceMoresevere–mayimpaircellularfunctionAharbingerofcelldeathNonalcoholicsteatohepatitismayleadtocirrhosisandevenhepatocellularcancerWhenmild–havenoeffectoncellularfunction

Morphology

Intracellularclearvacuoles:SudanIII/OilredOstaining24BrightYellow,SoftandGreasyFattyChangeinHepatocyteSmallvacuolesaroundnucleusClearedspacedisplacethenucleustotheperipheryofthecellFattycysts25Cholesterolandcholesterolestersaccumulation

SeveralpathologicprocessesAtherosclerosis

FoamCellsSudanIIIStainingcholesterol–ladenatheromasNormally,inmostcellsforsynthesisofcellmembrane26Xanthomas

Tumourousmassesproducedbycholesterol–ladenMacropahgesclusterinskinandtendonsAcquiredandhereditaryhyperlipidemicstatesInflammationandnecrosisCholesterolosisingallbladderNiemann-PickdiseaseLysosomalstoragediseaseEnzymeinvolvedincholesteroltraffickingismutatedCholesterolaccumulatesinmultipleorgans27ProteinsAccumulationPathogenesisExcessinamount

AbsorptiondropletsinproximalrenaltubulesRussellbodiesinplasmacells28CausesAnormalendogenoussubstanceis

produced

atanormalorincreasedrate,buttherateofmetabolismisinadequatetoremoveit.FattydegenerationinhepatocytesHyalinedegenerationinrenaltubularcellsAnormalorabnormalendogenous

substanceaccumulates,becauseofgeneticoracquireddefectsinthemetabolism,packaging,transport,or

secretion

ofthesubstance.StoragediseaseAnabnormalexogenoussubstanceis

depositedandaccumulates.Carbonortattooing29DefectiveintracellulartransportandsecretionERstressinducedbyunfoldedandmisfoldedproteinsAggregationofabnormalproteinsDefectsinStructure-ProteinFoldingDefectsNascentPolypeptideChainsProteininProperConfigurationPartiallyfoldedintermediatesstabilizedbymolecularchaperones30FamilialHypercholesterolemiaParkinson’sDiseaseCertainformsofAmyloidosisDefinition

Analterationwithincellsorinextracellular

space,whichgivesahomogenous,glassy,pinkappearanceinroutinehistologicsectionsstainedwithH&E.Hyalinechanges/degenerationAdescriptivehistologictermProducedbyavarietyofalterations,notrepresentaspecificpatternofaccumulation31

IntracellularhyalinechangesReabsorptiondroplets;Russellbodies;Malloryalcoholihyalin;Viralinclusions

ReabsorptiondropletsinrenaltubularcellsNumerouscoarseredgranules

withinthecytoplasmFrequentlyin

glomerulonephritis32RussellbodiesinplasmacellsRoundhyalineinclusions

withincytoplasmImmunoglobulinsHugelydistendERLargehomogenousinclusions33

ExtracellularhyalinHyalinedegenerationofarteriolesinlong-standinghypertension,duetoextravasatedplasmaproteinanddepositionofbasementmaterialHyalinedegenerationofconnectivetissue(inoldscar)

AmorphouspinkstainingmaterialonthewallHardeningofthewalland

narrowingofthelumenHyalinedegenerationofsmallarteriesinspleen34AmyloidosisDefinition:Aheterogeneousgroupofpathogenic

fibrillarproteinsaccumulatinginextracelluarspace.

EM:nonbranchingfibrilsofindefinitelengthanddiameterH&E:anamorphous,eosinophilic,hyaline,extracellularsubstanceNotasingledisease,onlyincommonthedepositionofsimilar-appearingproteins

ThreemajorandseveralminorbiochemicalformsOtherFeatures

LikelyrelatedtoabnormalproteinfoldingAsystemicdiseasethatmayinvolvecomponentsofimmunesystem

Withprogressiveaccumulation,encroachesonandproducespressureatrophyofadjacentcells35ChemicalNatureofAmyloidFibrils

Threemajorforms

AL(amyloidlightchainprotein):derivedfromplasmacellsandcontainsimmunoglobulin→monoclonalBcellproliferationAA

(amyloid-associatedprotein):synthesizedinliverandelevatedininflammatorystates

Aβ

amyloid,mainlyinAlzheimerdisease

Minorformsofamyloidfibrils

Beta-2-microglobulin(thecomponentofclassIMHCmolecules):inlong-termhemodialysis36ClinicalFormsofSystemicAmyloidosis

Primaryamyloidosis(B-celldyscrasia,AL)

BenceJonesprotein(monoclonallightchainsecretedinserumbyneoplasticBcellsandwillbeexcretedinurine)

Secondaryorreactiveamyloidosis(AA)Chronicinflammatoryconditions:bronchiectasis,chronicosteomyelitis,rheumatoidarthritis

Hemodialysis-relatedBeta-2-microglobulindeposition

Hereditary(AA)37Nodular(tumor-formingdeposits,B-celldyscrasia)

Endocrineamyloidosis(procalcitonin)Amyloidosisofaging:Heart,lung,pancreas,spleen,brainLocalizedAmyloidosis38AmyloidosisintheliverAmorphous,eosinophilic,hyaline,extracellularsubstance39

ExogenousCarbon:coaldust(urbanlife,inalveoliandregionallymphnodes);anthracosis;emphysema

Tattooing:residefortheremainderofthelife

Endogenous

Lipofuscin:wear-and-tearoragingpigment,notinjuriousMelanin:melanocytesBilirubin：normalpigmentinbile;derivedfromhemoglobinbutnoiron;normalformationandexcretionisvitalfor

health;jaundice

Hemosiderin

Pigmentation40MelaninBilirubin41HemosiderinHemoglobin-derived,goldenyellow-to-brown,granularorcrystallinepigmentinwhichironisstoredincellsiron+apoferritinFerritinmicellesHemosiderinaggregateproteinTheformironisstoredPhysiologicorpathologicLocalexcess:grosshemorrhage，monbruiseSystemicoverloadofiron：hemosiderosisBrightred(hemoglobin)Green

(biliverdin)Darkred(bilirubin)Goldenyellow(hemosiderin)42Hemosiderincoarse,gloden,granularpigmentlyingwithincytoplasmPrussianbluereaction,specificforiron43PathologiccalcificationDystrophicCalcificationMetastaticCalcificationlocallocalorsystemicdyingtissue(eg.atheroma,damagedheartvalves)normaltissuenormalserumlevelofcalciumhypercalcemiaDystrophiccalcificationindamagedheartvalve:fine,whitegranulesorclumps,feltasgrittydepositscalciumsaltinH&E:basophilic,amorphousgranular,sometimesclumped,appearance44CausesIncreasedsecretionofparathyroidhormone(PTH),Destructionofbonetissue,RenalfailureMetastaticcalcificationAffectingInterstitialtissueofgastricmucosa,Kidneys,Lungs,Pulmonaryveins,SystemicarteriesPsammomaBodySinglenecroticcellsareencrustedbythecalciumandprogressivelyacquireouterlayerscreatinglamellatedconfiguration45Reversiblecellinjuryvs.CelldeathNoprecisecut-offpointManyways,butnotallfatalPrimaryinjuryorrippleeffects?“Pointofnoreturn”isstilllargelyunderdetermined

TwophenomenacharacterizeirreversibilityInabilitytoreversemitochondrialdysfunctionProfounddisturbancesinmembranefunctionLeakageofintracelluarproteinsprovidesameansofdetectingtissue-specificcellularinjuryanddeathusingbloodserumsamples46FeaturesofTwoTypeofCellDeathNecrosisApoptosisRoleInvariablePathologicOftenphysiologic,MaybepathologicMechanismATPdepletion,Membraneinjury,FreeradicalsProgrammedCellDeathEndonuclease,GeneactivationNucleusPyknosis

→karyorrhexis→karyolysisFragmentationintonucleosomesizefragmentsCellsizeEnlarged(swelling)Reduced(Shrinkage)CellularContentsEnzymaticdigestion;MayleakoutofcellIntact;MaybereleasedinapoptoticbodiesNumberUsu.Massive,occ.SinglecellSinglecellorsmallclusterofcellsAdjacentinflammationFrequentNo47APOPTOSIS(Programmedcelldeath)

Literally,apoptosisinGreek:

,refertoeliminateunwantedorpotentiallyharmfulcellsandcellsthatareoutlivedtheirusefulness;alsoa

whencellsaredamaged(esp.DNA)beyondrepair.Pathologicevent“fallingoff”Numeroussituations

ProgrammeddestructionofcellsduringembryogenesisHormonedependentinvolutionoftissuesintheadultCelldeletioninproliferatingcellpopulations(intestinalcryptepithelia)andlymphoidorgansCelldeathinducedbycytotoxicTcells,adefensemechanism48

DNAbreakdown

：Endonucleases→

multiplesof180-200bpnucleosome-sizefragments→DNAladdersUntrastructuralFeaturesofApoptosis

ProteincleavagebycaspasesNuclearscaffoldCytoskeletalproteinDNAladders

Characteristicbutnotspecificforapoptosis,alsocanbeseeninnecrosis49Cellshrinkage：smallersize,densercytoplasm,moretightlypackedorganellesFormationofcytoplasmicblebsandapoptoticbodiesLackofinflammation：phagocytosisofapoptoticbodiesbyadjacenthealthycellsormacrophages50DefinitionofNecrosisDefinition:aspectrumofthemorphologicchangesthatfollowcelldeathinlivingtissue,resultingfrom

denaturationofintracellularproteinsandprogressivedegradativeactionofenzymesHowaboutcellsplacedimmediatelyinfixative?Theyaredeadbutnotnecrotic51

KaryolysisDNaseActivityThreePatternofNuclearChangesinNecrosis

----chiefmicroscopicindicatorsofcellularinjuryKaryorrhexisFragmentationofPyknoticNucleusPyknosis

DNACondensation52MorphologicAppearanceofNecrosisIncreasedeosinophilia

lossofRNAinthecytoplasmIncreasedbindingofeosintodenaturedcytoplasmicproteins

Moreglassyhomogeneousappearance

lossofglycogenparticlesVacuolatedandmoth-eatencytoplasm

cytoplasmicorganellesdigestedbyenzymesCalcificationofnecroticcells

lowerpH?53NecrosisClassificationCoagulativenecrosisDenaturation>>ProteolysisLiquefactivenecrosisProteolysis>>DenaturationGangreneBacterialinfectionsupervenesonnecrotictissueCaseousnecrosis

CompletedissolutionofnecrotictissueFatnecrosisAwellfixedterm,notaspecificpatternofnecrosisFibrinoidnecrosisMainlyinallergicandhypersensitivitystate54CoagulativeNecrosisofkidneyCoagulativeNecrosisDenaturationofbothstructuralandenzymaticproteinsbyinjuryorthesubsequentincreasingintracellularacidosis→ProteolysisisblockedPreservationofthebasicoutlineofthecoagulatedcellforatleastsomedaysCharacteristicfeatureofhypoxicdeathGrossly:firmtexture-dense，white，dryappearance55CaseousNecrosisAdistinctformofcoagulativenecrosis

Tuberculosis

Grossly:soft,cheesywhiteappearanceMicroscopically:completebreakdown

ofnecrotictissueintofinegranular

material,completelyobliterated

tissuearchitectureCaseousNecrosisofTBLymphNodeCaseousNecrosis56GangreneAsubtypeofcoagulationnecrosisDryGangreneofExtremityWetGangreneofSmallIntestineGasGangreneofDeepSoftPart57Liquefact