Emphysema Patofisiologi 2

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394 TheJournalofClinicalInvestigation http://www.jci.org Volume118 Number2 February2008

Molecular pathogenesis of emphysemaLaimute Taraseviciene-Stewart and Norbert F. Voelkel

Pulmonary and Critical Care Medicine Division, University of Colorado Health Sciences Center, Denver, Colorado, USA.

Emphysemaisonemanifestationofagroupofchronic,obstructive,andfrequentlyprogressivedestructivelungdis-eases.Cigarettesmokingandairpollutionarethemaincausesofemphysemainhumans,andcigarettesmokingcausesemphysemainrodents.Thisreviewexaminestheconceptofahomeostaticallyactivelungstructuremaintenancepro-gramthat,whenattackedbyproteasesandoxidants,leadstothelossofalveolarseptalcellsandairspaceenlargement.Inflammatoryandnoninflammatorymechanismsofdiseasepathogenesis,aswellastheroleoftheinnateandadap-tiveimmunesystems,arebeingexploredingeneticallyalteredanimalsandinexposuremodelsofthisdisease.Theserecentscientificadvancessupportamodelwherebyalveolardestructionresultingfromacoalescenceofmechanicalforces,suchashyperinflation,andmorerecentlyrecognizedcellularandmolecularevents,includingapoptosis,cel-lularsenescence,andfailedlungtissuerepair,producestheclinicallyrecognizedsyndromeofemphysema.

. . . animals have really two environments: a milieu exterieur in which the organism is situated and a milieu interieur in which the tissue elements live. All the vital mechanisms, varied as they are, have only one object: that of preserving constant the conditions of life in the milieu interieur. ClaudeBernard(1)

Emphysemaisdefinedasairspaceenlargementoftheadultlung(2)(Figures1and2),incontrasttodevelopmentallyimpairedalveolarizationoftheneonatallung.HumanemphysemawasoriginallydescribedbyRuyschinAmsterdamattheendofthe17thcenturyandinthe19thcenturybytheFrenchphysicianLaennec(3),whonotedmarkedvariationsinthesizeoftheairvesicles,whichmightbesmallerthanamilletseedoraslargeasacherrystoneorharicot.Vesiclesofthelattersizewerepro-ducedbythecoalescenceofadjacentairspacesfollowingrup-tureofthealveolarwalls(4).Emphysemamostfrequentlydevelopsbetweentheagesof45

and60asacomponentofchronicobstructivepulmonarydis-ease(COPD)insmokers(5),butemphysematouslungdestruc-tionhasalsobeenreportedinothernonsmoking-relateddisor-derssuchasHIV-1infection(6)orhypersensitivitypneumonitis(7).TheclinicalsyndromeofCOPDincludesbothpulmonarymanifestations, includingairflowobstruction, smallairwayinflammation(bronchiolitis),andlungparenchyma(alveolar)destruction(8);andextrapulmonarymanifestations,includingmusclewasting,osteoporosis,andanemia(911).Althoughspu-tumproductionandcougharefrequentsymptoms,themostdisablingaspectofsevereCOPDisbreathlessness(dyspnea).ThepresenttreatmentofCOPDconsistsofdailyadministrationofinhaledbronchodilatorsand/orsteroidsandoxygensupplemen-tation,oftencontinuouslyfor24hoursforhypoxemicpatients(12);thereisnoemphysema-specifictreatment.MortalityandmorbidityfromCOPDisanincreasinglyseriousglobalhealthproblem;COPDrankedsixthamongthecausesofdeathglob-allyin1990butisexpectedtobethethirdmostcommoncauseofdeathin2020(13).Inaddition,thehealthcarecostsofCOPDareconsiderable(14).

A smoking gun?Thequestionofwhethercigarettesmokingisacauseofemphy-semawasraisedinthe1950s(15),andthelandmarkstudybytheBritishepidemiologistsFletcherandPetosupportedtheconceptthatchroniccigarettesmokingisindeedthemajorcauseofchron-icbronchitisandemphysema(16).Morerecently,aconsensushasbegunbuildingthatthelungstructureisattackedanddestroyedbyinhalednoxiousagentscontainedincigarettesmokeorinpol-lutedair;theeffectsofexposuretodieselexhaust,ozone,andmicroparticlesarebeingexamined(1719).Thereisalsoagree-mentthatnoteverylong-termheavysmokerdevelopsemphysemathepainterPabloPicasso,whostartedsmokingasateenagerbutremainedactiveandproductivebeyondhisninetiethyear,comestomindandthatgeneticsusceptibilityfactorsunderlieemphy-semadevelopment(20).Onealternativeconceptofemphysemapathogenesisisthatthediseaseisamanifestationofprematureagingofthelung;genepolymorphismsarebeinginvestigated,andresearchersaresearchingforcandidategenesthatencodeproteinsthatarecomponentsofinflammatorypathways(21),antioxi-dants,andproteolysisinhibitors(20,22,23).Manyaspectsofthepathobiologyofhumanemphysemaremainunclear.Forexample,ithasbeenrecognizedformanyyearsthathumanemphysemacanaffecttheentirelungorhaveapredilectionfortheupperlobesandsubpleuralareas.Thereasonsfortheseregionaldifferencesinemphysemadistributionarenotunderstood(23).Evidenceofbothemphysemaandpulmonaryfibrosisinthesamepatienthasbeenreported,implicatingsomecommonpathwaysleadingtothedifferentoutcomes(24,25).Itremainslikewiseunresolvedwhyemphysematouslungdestructionisrelentlesslyprogressiveinsomepatientsevenmanyyearsaftersmokingcessation.Thedestructionofalveolar-capillary(epithelialandendothelial)

cellsbyproteolyticenzymeshasbeengenerallyacceptedasoneoftheprinciplemechanismsofdestructiveairspaceenlarge-ment(Figure3),basedonthedemonstrationthatintratrachealinstillationofthecysteineproteasepapain(ameattenderizer)causedemphysemainrats(26)andonanassociationbetweenemphysemaandageneticdeficiencyintheneutrophilelastaseinhibitora1-antitrypsin(AAT)(27).Whereasalargenumberofanimalstudies,whichmakeuseofspontaneousorengineeredgeneticvariations,supporttheinflammation-proteolysistheory,somestudieshaveraisedquestionsaboutwhetherinflamma-torymechanismsaresufficientornecessarytoexplainairspaceenlargementperse,andotherpathogeneticmechanismsofthis

Nonstandardabbreviationsused:AAT,a1-antitrypsin;COPD,chronicobstructivepulmonarydisease.

Conflictofinterest:Theauthorshavedeclaredthatnoconflictofinterestexists.

Citationforthisarticle:J. Clin. Invest.118:394402(2008).doi:10.1172/JCI31811.

Downloaded on December 9, 2013. The Journal of Clinical Investigation. More information at www.jci.org/articles/view/31811

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TheJournalofClinicalInvestigation http://www.jci.org Volume118 Number2 February2008 395

diseasearebeingconsidered(2831)(seeAdaptive immunity in emphysema).Althoughemphysemaisonlypartoftheradiograph-icandhistologicalpresentationofCOPD,thisreviewfocusesonalveolarseptumdestructionandairspaceenlargementandwillhighlightanumberofdifferentpathogeneticmechanismsthatcanbeunderstoodtooperateindividuallyorinconcert.Wealsoattempttointegratetheincreasinglylargeandgrowingnumberofmoleculartargetsthathavebeenexperimentallyinvestigatedandshowntocauseairspaceenlargement.Forfur-therinformation,wereferthereadertorecentcomprehensivereviewsonthepathogenesisofemphysema(32,33).

Adult lung structure maintenance programThelung,liketheskinandthegut,hasalargesurfaceareathatisconstantlyexposedtotheenvironmentandisalsoametaboli-callyactiveorganwithalargeblood-airinterfacedesignedforbothgasexchangeandcapillaryendothelialcellprocessingofamyriadofendogenoussubstances.Thisdualfunctionofgasexchangeandmetabolismcanonlybemaintainedthroughoutadultlifeifthestructureoftheorganishomeostaticallymaintainedanddefendedagainsttheexternalandinternalenvironment.Amod-

ernconceptisthatbothresidentandbonemarrowderivedstemcellsparticipateinthemaintenanceoftheadultlungstructure.Ourknowledgeoflungcellturnoveranddependenceonextrapul-monaryrepairmechanismsatpresentisrudimentary.However,itisconceivablethataprogramoflungstructuremaintenanceofcriticalimportanceduringlungdevelopmenthasretainedandpreservedarchitecturalbuildingprinciplesandthat,laterinlife,elementsofthisdevelopmentalprogramareutilizedtoprotectthelungagainstdestruction,antioxidants,antiproteases,andattackbytheinnateimmunesystem.Furthermore,itispossiblethatdestructionofthelungparenchymamayresultifthereischronicunopposedoxidantstress,unopposedproteolysis,apoptosis,andimpairedclearanceofapoptosedcellbodies(3437),cellularsenes-cencewithoutadequatecellreplacement(38,39),oraswitchfromaninnatetowardanautoimmuneresponse(40).

Pathology of human emphysemaAsstatedabove,thepathologyofCOPDrelatestoinflammato-rychangesinthesmallairwaysandtothelossofalveolarseptalstructuresandsmallvessels(41).Thealveolarseptaeareinfiltratedbyneutrophils,clustersofCD68+macrophages,andlymphocytes.ArecentstudybyHoggetal.(42)providedaquantitativecellularanalysisoflungtissuesamplesfrompatientswithCOPDofalldegreesofseverityandlungfunctionimpairment.ThepresenceoflymphfolliclesintheparenchymaordendriticcellinfiltrationandTh1cellswasnoted,raisingquestionsaboutthenatureoftheimmuneresponseanditspotentialroleinemphysematousdestruction.Onecontemporarypathogeneticmodelofemphy-semahasbeenbuiltonthedataprovidedbymanylaboratories(Figure3).ThismodelpositsthatneutrophilelastaseandMMP-12releasedbyactivatedmacrophagesenzymaticallydestroytheelas-tinscaffoldofthealveolarspaces.However,theproductionofproteasesisnotrestrictedtoinflammatorycells;structuralcellssuchasepithelialandendothelialcellsarealsocapableofproduc-

Figure 1Normal versus emphysematous alveoli.

Figure 2Human emphysema. (A) Chest CT scan of a 56-year-old man with COPD demonstrating a profound loss of the lung parenchyma and paucity of lung vessels. (B) Whole-lung section demonstrating ubiq-uitous holes, i.e., emphysema. (C) Histology of end-stage emphy-sematous lung. H&E staining; magnification, 40. The loss of alveo-lar septal cells is not accompanied (in this specimen) by significant inflammatory cell accumulation.




ingproteases(43,44).Elastinfragmentsinturnarechemotactic(45)andattractinflammatorycellstositesofinjury,thussuggest-ingajointroleofinflammatorycellsandproteases.Strongexperi-mentalsupportofthisconceptisprovidedbydatashowingthateliminationofalveolarmacrophagesinrats(46)andknockoutofMMP-12inmice(47)protectedtheseanimalsagainstcigarettesmokeinducedemphysema.Althoughthepresenceofinflammatorycellsthatcanreleaseoxi-

dantsandproteaseshasnowbeenwelldocumented,oneisremind-edthatanumberofacutelungdiseasesthatmanifestwithmassiveinflammation(suchasbacterialpneumoniaandacutelunginjury)developandresolveentirelywithoutemphysematousparenchymadestruction.Figure2Cshowsasectionofahumanlungwithsevereairspacedestructionyetinflammatorycellsareabsent;thisdoesnotimplythatinflammatorycellswerenotpresentearlierorthatlungstructuralcellssecretedestructiveproteases.

Animal models of emphysemaCananimalmodelshelpustoresolvetheissueofwhetherinflam-mationisnecessaryinemphysemapathogenesis?Inflammationisdefinedasthepresenceofinflammatorycellsandalteredlevelsofmediatorsofinflammationintheparenchyma.Rodentemphy-semamodelscanperhapsbebroadlycategorizedas:(a)geneticmodels,whichviatheuseofgenemanipulationssuchasgeneoverexpressionorknockout,canbeutilizedtoidentifytheusu-allysilentandhiddenactionsofelementsofthelungstructuremaintenanceprogram;and(b)exposuremodels,whichinvolveinducingdamagetotheadultlungofwild-typeortransgenicanimals(Tables1and2)andexplorethemechanismsofcellular

damageandprotection.Manyoftherecentlydevelopedexperi-mentalmodelsofemphysemasmoking-relatedornotshowthatinflammatorycellsofvaryingcompositionspopulatetheair-spacesinincreasednumbers(48,49).Yeast,worm,fly,andmousemoleculargeneticanalysisand

engineeringallowustodissectelementarybiologicalmecha-nisms,butinthelongrunitmaybeunproductivetoassumethatalltheimportantproblemsofhumanlungpathobiologycanbesolvedinthemouse,foratleastfourdifferentreasons.Themouselunghasnosystemicpressurebronchialcirculation;themouselikelydoesnotpossessmanyofthecytochromeP450genesthatgovernhumantoxicology;andtherearemanyimpor-tantdifferencesinthefunctionoftheimmunesystemsofmiceandhumans.Last,rodentsmayhaveandmayusetheoptionofperpetuallunggrowth.

Proteases and AATProteasescanenzymaticallydegradeavarietyoflungmatrixpro-teins,andantiproteasesprotectagainsttheirdegradation.Thetopicofproteasesandantiproteasesandtheirrolesinvariousemphysemamodelshasrecentlybeenreviewed(50).Asthenum-berofreportedelastases,MMPs,cathepsins,andknownactionsofcaspases(51)issteadilyincreasing,itbecomesapparentthatthestructuremaintenanceprogrammustfunctionwithbothproteasesandantiproteases(reviewedinrefs.52,53).Theactivityofinflammatorycellreleasedproteasesisinhibitedbyantipro-teases,whileotherproteasesinalveolarseptalstructurecellsareengagedintheongoingworkofrepairandangiogenicremodel-ingandjointheneutrophilandmacrophageelastasesinsupportoftheinnateimmuneresponse.AlthoughFigure3schematicallydepictsanelastin-basedaspectoflungtissuedestruction,alargenumberofreportshavealsoemphasizedaroleofcollagenasesanddescribedcollagenbreakdowninemphysemaandemphy-semamodels(5458).Otherknownfactorssuchasbreakdownofhyaluronanbyreactiveoxygenspeciescanalsocontributetotheinflammatoryeffects,whileaerosolizedhyaluronanpreventsair-spaceenlargementinamousemodelofcigarettesmokeinducedpulmonaryemphysema(Table2).ThefactthatanullmutationofthegeneencodingtheelastolyticcysteinecathepsinSprotectedmiceagainstIFN-ginducedemphysema(59)illustrateshowcom-plexpotentiallyproteolyticlungdestructionmaybe,particularlygiventhelargenumberofenzymesaswellastheirtargetsmanystructuralproteins.Forexample,cathepsinSaffectstheproduc-tionoftypeIVcollagenderivedantiangiogenicpeptides(60).Manyquestionsremainunanswered.Onefundamentalques-tionrelatestothefunctionalandtemporalinteractionsamong

Figure 3Proteolytic destruction of the elastin fiber network by cigarette smokeactivated inflammatory cells. This schematic illustrates the dense elastin fiber network in the lung; the elastin fibers form a par-ticularly dense network around lung capillaries. Neutrophils, macro-phages, and dendritic cells have been recognized as producers of proteases. In addition to neutrophil elastase and MMP-12, there have been a myriad of proteases identified in human and animal emphy-sema that can degrade elastin, collagen, and fibronectin. Loss of the alveolar septal scaffold after enzymatic degradation of various matrix proteins causes airspace enlargement. Elastin peptides are chemotactic and can attract additional inflammatory cells into the lung, thus generating a vicious cycle.




proteolysis,oxidantstress,andcaspase-dependentand-indepen-dentapoptosisintheepithelialcells,endothelialcells,andmac-rophagesofthealveolarspaces.Forexample,inarodentmodelofemphysema,broad-spectrumcaspaseandMMPinhibitorsandantioxidants(36,61,62),aswellasAAT,(63)inhibitapoptosis,suggestingthatsomepowerful,perhapsmutuallyenhancinginteractionsbetweenproductsofproteolysis(cleavedproteinfragments?)andoxidantstressculminateinendothelialandepi-thelialcelldeath(64).SinceAATcanstoptheviciouscycleofoxi-dantstress/proteolysis/apoptosis,andprotectagainstexperimen-talemphysemainrodents(65),Tudersgroupexploredwhetherthisusuallyveryabundantplasmaproteininhibitscaspaseactiva-tion.Indeed,AATinducedtheinhibitionofcaspases,whichwasassociatedwithreducedoxidantstressinvivoandalsoinculturedendothelialcells(66).Again,anewconceptisemerging:thatAAThasadditionalactions(67)thatareclearlyunrelatedtoitswell-studiedenzymaticantineutrophilelastaseactivityandthatitpro-tectsendothelialcellsagainstoxidants.

Innate immunity and oxidative stressInnateimmunityreliesonpatternrecognitionreceptorsthatrec-ognizemolecularstructurescommontomanymicroorganisms,suchasLPSandendogenousligandssuchasheatshockproteins.ActivationofTLR4byLPStriggersproductionofbothcytokinesandreactiveoxidantspecies.Alterationsoflungcytokines,oxidantstress,andTLRsignalinghaveallbeenassociatedwithexperi-mentalemphysema.Forexample,lung-specificoverexpressionofTNF-ainmicecausesemphysemaandsomedegreeofpulmonaryhypertension(68).Knockoutoftheantioxidanttranscriptionfac-tornuclearerythroid-relatedfactor2(Nrf-2),whichamongothergenesregulatestheexpressionofglutathioneperoxidase2(69),mademicesusceptibletocigarettesmokeexposure;theydevel-opedairspaceenlargementaswellasmorepronouncedinflam-mationandapoptosisofalveolarseptalepithelialandendothelialcells(70).Inamanneranalogoustothewayinwhichelimina-tionofanimportantantioxidantswitchboardupsetsthelungcelloxidant/antioxidantbalance,alterationsoftheTLRsystem

maychangetheinteractionsofthelungwiththemilieu exterieur. Zhangetal.(31)followedTLR4-knockoutmice(Tlr4/mice)intomiddleageandfoundthattheanimalsspontaneouslydevelopedemphysemaassociatedwithanoxidant/antioxidantimbalanceduetoincreasedNox3(anovelNADPHoxidase)geneexpressionandelastindegradation.Interestingly,theelastinbreakdownwascausedbyoxidants,sinceNADPHoxidoreductaseinhibitionpre-ventedtheelastinbreakdown.Alsoofinterest,theTlr4/micedidnotshowinfiltrationofthelungparenchymawithinflammatorycells,andtheauthorsspeculatethatthesourceofoxidantsandofproteolyticactivitymaybethealveolarseptalendothelialcells.Anewconcepthasthusemerged:theremaybeaTLR4tone(andperhapsamoregeneralTLRtone)thatprovidesalow-gradeactivationoftheinnateimmunesystemthatisrequiredforday-to-daylungstructurestability.ThiswouldmakeTLR4anintegralelementofthelungstructuremaintenanceprogram(71)bycon-tributingtothedefenseofendothelialcellsagainstoxidantsandalsoviaTh2cellactivation(72).OthersolubleinnatehostdefensemoleculessuchassurfactantproteinDareassociatedwithregula-tionoflocallunginflammatorymilieu,andtheknockoutmicedevelopemphysema(Table1).SphingolipidshaverecentlyreceivedattentionsincePetrache

et al. (73) found elevated levels of long-chain ceramides inhumanemphysematouslungs,increasedceramidelevelsintheVEGFRblockaderatemphysemamodel,andinhibitionofapop-tosisandemphysemaaftertheuseofneutralizinganticeramideantibodies.Incontrasttotheproapoptoticceramides,sphingo-sine-1phosphatemay,insuchascenario,serveasabalancingprosurvivalfactor.

Adaptive immunity in emphysemaFinally,theremaybeadditionalmechanismsatplayintheslow,progressivedestructionofthelungparenchyma,whichcancontin-uefordecadesaftersmokingcessation.Whatsustainsthechronicinflammationforyearsaftersmokingcessationcontinuestopuz-zleinvestigators.Chronic,poorlycontrolledasthmainhumansisassociatedwithlungremodelingandatransitiontofixedair-

Table 1Genes involved in airspace enlargement in mouse models of emphysema

Gene Result Ref.

OverexpressionmodelInterleukin 1b (Il1b) Inflammation, fibrosis S22, S23Interleukin 4 (Il4) Eosinophilic infiltration, fibrosis 87Interleukin 13 (Il13) Inflammation S24Interferon g (Ifng) Inflammation S25Tumor necrosis factor-a (Tnfa) Chronic inflammation 68KnockoutmodelVegf conditional KO Absence of inflammation 102Surfactant-associated protein D (Sftpd) Foamy macrophages S26Toll-like receptor 4 (Tlr4) Increased oxidant generation and elastolytic activity 31Tissue inhibitor of metalloproteinase 3 (Timp3) Spontaneous progressive air space enlargement S27Fibroblast growth factor 23 (Fgf23) Premature aginglike phenotype S28b6 subunit of avb6 integrin Age-dependent emphysema S29Smad3 Age-related emphysema S30, S31Klotho Imbalance of MMP-9 and TIMP-1 S32, S33Signal transducer and activation of transcription (Stat3) High susceptibility to viral infection S34




wayobstruction.Whetherorhowthisfixedairwaydestructionrelatestoalveolardestructionisunclear.Whereasallergicasthmaisunderstoodtobeanimmunedisorderwhereintheantigenissometimesknown,andanimalmodelsofasthmadevelopedusingavarietyofimmunizationstrategiescanbedissectedtouncovermultiplelayersoftheadaptiveimmuneresponse,emphy-semauntilrecentlyhas,asdiscussed,beenseenasaproblemofproteolysis,notofadaptiveimmunity.Whilethisissomewhatperplexingbecausetheburningcigarettecanbeseenasanantigendeliverydevice,mostrecentlyaconceptofemphysemapathogen-esisbasedonimmunemechanismshasbeguntoemerge.Afewelementsofthisconceptarediscussedhere.Lunggeneexpressionprofilingofcigarettesmokeexposedratsdemonstratedasus-tained,increasedexpressionofanumberofgenesimplicatedintheinnateandadaptiveimmuneresponses(74).Chroniclungcelldamage,andinparticularapoptosis,whencombinedwithineffec-tivephagocyticremovalofapoptosedcellbodies(37)mayresultinthegenerationofneoantigens(forexample,nucleosomesorDNAfragments;ref.75),peptides(76),andautoantibodies.BothCD4+andCD8+Tlymphocytesareabundantlypresentinemphysema-touslungs(30,42,77),asareBcells,arrangedalsoinlymphfolli-cles(40,42).Comparisonscanbedrawnwithrheumatoidarthritis(28),anotherslowlyprogressiveinflammatorydiseasewhereinBcellfolliclesareprevalent.Inaddition,tobaccoanti-idiotypicanti-bodieshavebeenidentifiedinserumfromsmokers(78)andanti-elastinantibodiesinserumfrompatientswithemphysema(79).Basedonstudiesdesignedtodestroytumorvesselendothe-

liumby immunizingmicewithxenogeneicHUVECs (80),weimmunizedratswithHUVECswiththeintentofattackingthepulmonaryendothelium(44).Inthismodel,intraperitonealinjec-tionofendothelialcellscausesemphysema,activationofMMP-2and9,andgenerationofantiendothelialcellantibodies.Thismodelprovidesproofofconceptforanautoimmunemechanism

ofendothelialcellapoptosisinthedevelopmentofemphysema,becausetheemphysemacanbepassivelytransferredtonaiveani-malsfollowingadministrationofeitherCD4+TcellsorserumfromHUVEC-immunizedrats.Ifdetectedinpatientswithemphysema,antiendothelialcellantibodiesconceivablycouldexplainthelossofcapillariesnotonlyinthelung,butalsoinskeletalmuscle,aswellasthemusclewastinginpatientswithCOPD-emphysema.Interestingly,HUVEC-immunizedratsinjectedconcomitantlywiththeTLR4ligandlipidAareprotectedagainstlungcellapop-tosisanddonotdevelopemphysema(81).Reportsthatsmokingdecreasesthenumberoflungtissuedendriticcells(82)butalsothatsmokinginducesanincreaseinthenumberofairwayden-driticcells(83)havebeenpublished.Inaddition,smokingcausesTLR4-dependentdendriticcellactivation(72).Atpresenttherearenodatathatprovidesolidevidenceinsup-

portofanautoimmunepathogenesisofhumanemphysema,butatleastwecanseethehorizon,andtheevidenceseekersarearmedwithcriteriaconsistentwithmodifiedKochspostulatesforautoim-munediseases(84):namely,thatemphysemadevelopsinthepres-enceofpathogenicCD4+Tcells,thatadoptivetransferofCD4+Tcellsresultsinemphysema,andthatemphysemadoesnotoccurintheabsenceofCD4+Tcells(44).Althoughsmokinghasbeenidenti-fiedasariskfactorforthedevelopmentofautoimmunediseases,itisunknownwhethersmokingcangenerateantiendothelialcellorantiepithelialcellantibodies.Perhapsaproductivesearchcanfol-lowtheleadofarthritisresearch,forwhichantibodiesagainstcitrul-inatedproteins(whicharehighlyspecificforrheumatoidarthritis)havebeenfoundinalmosteverypatient(85).Otheraspectsoftheinvolvementoftheimmunesysteminthepathogenesisofemphy-semacanperhapsbeexaminedinthesettingofpulmonarycapil-laritis,adistinctinterstitialreactionassociatedwithdiffusealveo-larhemorrhage(86).Clearly,thetoolsareavailabletopursueandexplorethehypothesisofautoimmuneemphysema.

Table 2Rodent models of emphysema

Species Trigger Result Ref.Guinea pig Cigarette smoke Emphysema and vascular remodeling 98, S14Rat Cigarette smoke Protected by simvastatin S18Rat VEGFR blockade Protected by caspase inhibitor, 36, 6163 protease inhibitor, antioxidantsRat HUVEC injection Both antibodies and CD4+ T cells 40, 44 can transfer the diseaseMouse Neutrophil elastase Protected by protease inhibitor S35Mouse Cigarette smoke Protected by AAT and by S36, S37 aerosolized hyaluronanMouse Macrophage elastase (MMP-12) Protected against cigarette smoke 47 induced emphysemaMouse, Nuclear erythroid 2 Cigarette smoke, elastase instillation Enhanced emphysema S38, S39 p45-related factor 2 (Nfr2) KMouse, CuZn superoxide Cigarette smoke Protected against emphysema S40 dismutase (CuZnSOD) overexpressionMouse, hemeoxygenase 1 overexpression Cigarette smoke Protected against emphysema S41Mouse, TNFa receptor (TNFaR) KO Cigarette smoke Protected against emphysema S42, S43Mouse, senescence marker Cigarette smoke Protected against oxidative stress 111 protein30 (SMP-30) KO associated with aging and smokingMouse Caspase-3 instillation Alveolar wall destruction 29Mouse Cigarette smoke Protected by phosphodiesterase 4 S13 (PDE-4) inhibitor Roflumilast




Intwodifferentmousestrainswithlung-specificoverexpres-sionofIL-4(Th2-proneBALB/candTh1-proneC57BL/6mice),onlytheTh1-proneC57BL/6straindevelopsaninflammatoryemphysematousandfibroticphenotype(87).Inaremarkableseriesofexperiments,theauthorsshowedthattheeffectsofIL-4overexpressionwerenotduetooverexpressionofTh2cytokines,butthatIL-4overexpressionaffectedlungTGF-b1andAATlev-elsandreducedadenosinedeaminaseactivity,leadingtoafoldincreaseinadenosinelevels.Interestingly,adenosinedeaminasedeficientmouselungsshowinflammationandalveolarspaceenlargement(88),adenosinecausesendothelialcellapoptosis(89),andindeedtheauthorscoulddemonstratethattreatmentwithadenosinedeaminasereducedinflammation,emphysema,andfibrosisintheIL-4overexpressingC57BL/6mice(87).Thus,thistransgenicmousestudytiestogethergeneticsusceptibility,immuneresponse,andlungpathology.HighexpressionofIL-4has indeedbeen reported inhuman emphysema lungs (90).Whetheradenosinedeaminaselevelsoractivityareincreasedinhumanemphysemaisunknown.

No VEGF, no growth only deathAlthough it ispremature todelineateaparticularmolecularsequenceofeventsthatbeginswithsomeformofmitochondrialstressandendswithdeathofalveolarseptalstructurecells,col-lectivelythedataindicatethatoxidantstressoccursandthatthereisindeedproteolysisandapoptosis.Bothepithelialcellsandendothelialcellsdie,andtheirapoptosishasbeendemon-stratedinhumanandanimallungs(34,62,9193).Thelossofalveolarcapillaryendothelialcellsandofsmallcapillaries(94)defacto makesemphysemaalsoavasculardisease(9599).However,whetherthelossofthestructure-supportingmatrixisprimaryandbegetsepithelialcelldeath,whichinturnleadstoendothelialcelldemise,remainsunresolved.Thepleiotropicarchgrowthfactor,VEGF(itsroleinthelunghasbeenrecentlyreviewed;

ref.100),isnormallyabundantlyexpressedintheadultlungtis-sue.Itsreceptor,VEGFR2(alsoknownasKDR),is,atleastintherat(101),expressedonbothepithelialandendothelialcells,andVEGFRblockade(62)orconditionalknockoutoftheVEGFgene(102)causeslungcellapoptosisandemphysema.BothVEGFligandandVEGFRexpressionarereducedinhumanemphyse-matouslungs(92).Asintheisletcellapparatusofthepancreas(103)andintheglomeruliofthekidney(104),alveolarseptalendothelialcellsmayvitallydependonparacrineandautocrine(105)VEGFsurvivalsignalsandmaybevulnerabletoVEGFRblockadeorVEGFwithdrawal(106).Inaddition,VEGFsignalingleadstoendothelialprostacyclinsynthesis(Figure4),andlossofprostacyclinsynthaseexpressionintheendothelialmonolayersofsmallpulmonaryarteriesinemphysematouslungsanddecreasedprostacyclinsynthesis(107)mayputthesecellsintodoublejeop-ardyandmayremoveyetanotherlungcapillaryendothelialcellsurvivalfactor.EffectivetranscriptionoftheVEGFgenemaybehamperedbyoxidativeDNAdamageofthehypoxia-induciblefac-tor1a(HIF-1a)responseelementoftheVEGFpromoter(108).Giventhebombardmentofthecellsinsmokerslungswithoxi-dants,onecouldeasilyembraceaVEGF/endothelialcellcentrichypothesisofemphysema.However,weshouldacknowledgethatwhilethissectionfocusesonVEGF,othergrowthfactorsandsignalingmoleculesalsoplayaroleinemphysemapathogenesis.GeneexpressionstudiesoflungsfrompatientswithCOPD(109)suggestthatthecellsintheseend-stagelungsarefundamentallycompromisedbecauseofimpairedmitochondrialenergymetab-olismandimpairedproteinsynthesis.Theprecisemechanismsofthismetabolicsyntheticfailurearenotunderstood,butpost-translationalproteinmodificationsandimpairedtranscriptionduetoDNAdamagecometomind.

Cellular senescenceInadditiontooutrightcelldeath,wehavetoconsideraroleofcellularsenescence(nottobeconfusedwiththenormalagingprocessof the lung)aprocessof replication fatigue inemphysema(110),asthereismountingevidencethatcellularsenescencemaycontributetoemphysemapathogenesis.Satoetal.(111)showedthatcigarettesmokeexposurecausedair-spaceenlargementinsenescencemarkerprotein30knockout(SMP30-knockout)mice (SMP30 is amultifactorialproteinthatprotectsagainstaging),andTsujietal.(39)demonstratedoverexpressionofthecellularsenescencemarkerp16andtelo-mereshorteninginalveolartypeIIcellsandendothelialcellsinthelungsofsmokerswithemphysema.Cigarettesmokeextractinducescellularsenescenceofnormalhumanfibroblasts(38).Ofinterest,senescentcellsmaycontributetothechronicityofinflammation.Senescentcellsstopsynthesizingproteins,andthisaspectmaybesharedbyconditionsofstarvation,which,

Figure 4One pathway likely involved in lung cell structure maintenance. VEGF gene expression is controlled by hypoxia-inducible factor 1a (HIF-1a). In endothelial cells, synthesis of prostacyclin (PGI2) and NO is one out-come of VEGFR activation. Reactive oxygen species can damage the promoter region of the VEGF gene and thus impair VEGF transcription. Activation of VEGFR2 induces NO production. NO and PGI2 promote endothelial cell survival. While it is known that VEGFR2 activation pro-motes NO production, the link between VEGFR2 activation and PGI2 synthesis still needs to be established.




likelybyaffectingproteinsynthesis,causespotentiallyreversibleemphysema(112).ResultsofearlystudiesbyMassaroandcol-leaguesinrats(113)arenowreflectedintheradiographicallydocumentedemphysemainpatientswithanorexia(114).Recentdataindicatethatstarvationcauseslungcellapoptosis(112),butstarvation-inducedemphysemawasnotaccompaniedbyinflam-mation;neitherwasthealveolarseptumdestructioncausedbyintratrachealinstillationofactivecaspase-3(29).Whetherthiscaspase-3inducedemphysemamodelalsodisplaysfeaturesofimpairedphagocytosisofapoptosedcellbodiesisunknown.

Can there be repair?Lungrepairandrestitutionoffunctionaretheholygrailofmod-ernlungbiology.Atpresent,thewinningargumentsarewiththosewhomaintain:itcantbedone,itwontwork.Thelossofthedenselywoven,well-organizednetworkofcollagenandelastinfibers(Figure3)onwhichalveolarepithelialandendothelialcellsitmaybecriticalandrepair-limiting(115).Inaddition,thedam-agedlungmayremembertheaccumulatedinflictedinjury.Forexample,indamagedskin,colocalizationofelastinandtheoxida-tivestressmarker4-hydroxy-nonenalhasbeenidentified,aswellascolocalizationofelastinandthecelltoxinacrolein(116).Althoughacroleincanupregulateendothelialcellhemeoxygenase-1(117),itisalsooneofthemostchemicallyreactivealdehydesinhaledwithcigarettesmoke(118),andlysyl-acroleinatedproteinshavebeendetectedinplasmasamplesfromsmokers(119).Acrolein-DNAadductsmaypreventthereturntonormallungcellfunction;somayasmoking-inducedimbalancebetweenhistonedeacetylationandacetylation(120,121).Whatabouttheideathatthebonemarrowcanrepairthelung?

Indeed,smallnumbersofbonemarrowderivedcellshavebeenidentified intheadulthuman lung(122).Forbonemarrowderivedprecursorcellstorepairtheinjuredlung,severalcondi-tionsmustbemet:(a)precursorcellsmustbeavailableinthemar-row;(b)precursorcellsmustbemobilizedfromthebonemarrowandtraffictothesiteofinjury;and(c)theprecursorcellsmustbeintegratedintotheexistinglungstructure,divide,anddifferenti-ate.Itmaybepossibletoexamineallofthesestepsintheadultandeventhesenilemouse.Butinemphysemapatients,thesemecha-nismsmaybeimpaired.Inthehumanlong-termsmoker,themar-rowprecursorcellpoolmaybereduced(123)andVEGF-depen-dentprecursorcellmobilization(124)maybeimpaired.Atpresenttheissueofhematopoieticcellsrepopulatingthelungafterinjuryremainscontroversial(125,S1)(seeSupplementalReferences;sup-plementalmaterialavailableonlinewiththisarticle;doi:10.1172/JCI31811DS1).Ofnote,inflammatorylipidmediators,likeleu-kotrieneB4,maycontroltheproliferationofsomestemcellpopu-lations(S2),againperhapspointingtowardapotentiallyhomeo-staticroleofsomeelementsoftheinflammatoryrepertoire.Mostlikely,chroniccigarettesmokingaltersthegeneexpressionpatternofalldifferentcelltypesofthelung(S3,S4).Hogansgroupinvestigatedthecontributionofciliatedcellsin

therepairofnaphthalene-injuredairwaysandfoundthatciliatedcellsdonotproliferateortransdifferentiateaspartoftherepairprocess(S5).Sidepopulationcellshavebeenfoundintheratlung(S6),buttheirroleinlungrepairisunclear.

Conclusions, further questions, and outlookEmphysemaresearchisgoingstrongandgoingforward.Contro-versialissuesrangingfromhowtomeasureairspaceenlargement

accurately(S7)andhowtodefineagingofthelung(S8)arebeingraisedanddebated.Transgenicmousestudieshaveuncoveredafewofthefacetsand

innerworkingsofthelungstructuremaintenanceprogram(S9);however,wedonotunderstandhowsomanydifferentgeneticmanipulationsresultinemphysema.Thismaintenanceprogram,sowebelieve,hasapurposeandisdesignedforhomeostasisbal-ancingcelllossandcellregeneration.Thecomplexityofthispro-gramispresentlybeyondourcomprehension,asnewcomponentsoftheprogramarebeingdiscoveredonanongoingbasis.Themaintenanceofthestructureisnotonlyjeopardizedbyamul-titudeofproteases;notonlycanthedefenseagainstoxidantsbeoverwhelmedbyceramide(73),butmyeloperoxidase-derivedprod-uctssuchasacrolein(S10)maymodifyproteinsandDNA,thusgeneratingapermanentrecordofenvironmentalandendogenousstress.Celldeath,nowacceptedasacauseofemphysema,mayoccurinthelunginavarietyofscenarioswhenstresspathwayshavebeenactivatedbeyondapointofnoreturn.Whereexactlyisthispoint?Ifinterventionwiththegoaltopreventcelldeathwerefeasible,woulditpreventortreatanautoimmunediseasecompo-nentbutleadtocancer?Breakdownofstructuremaintenancemayalsoleadto,ormaybe

associatedwith,repairfailure.Conceptually,thefailuretorepairtheadultlungiscausedbyanimpairmentofresidentlungstemcells,theimpairedmobilizationofprecursorcellsfromthebonemarrow(S11),orafailureofintegrationofadequatelymobilizedbonemarrowderivedprecursors(S12)intotheresiduallungtis-suebecauseofapermanentlossofthescaffold.Intuitively,preventionofemphysema(S13)orperhapsdisease

arrest(S14)appearstobeamoreachievablegoalthanreversalofoftenmassivelungstructuredamage.TheimpactofdietonCOPDhasbeenconsidered(S15).TheMediterraneandiet,inparticulartheconsumptionofoliveoil,mayprotectDNAagainstoxidativedamage(S16),resveratrolmayinhibit inflammatorycytokinerelease(S17),andfishconsumptionmaylimitthelungdamagecausedbysmoking(S18).Dietarymanipulationshavesuccessfullybeentestedinrodentmodels(S19),anddrugssuchasstatins(S20)alsoshowaprotectiveeffectinCOPDpatients(S21).Intheaggregate,thefieldofCOPDandemphysemaresearchhas

beenverymuchenergizedinthelastdecade.Aspiritofenterpriseandhopeforimprovingthelivesofmillionsofpatientssufferingfromthisdiseasehasemergedinboththeclinicandthelaborato-ry.Patientswithsmoking-relatedCOPD/emphysemaandpatientswithemphysemaofunclearetiologyalikeareexpectedtobenefitfromthishopefulchange.Futureresearchwillsurelyincreaseourunderstandingofboththecellularandmolecularmechanismsatworkduringnormallungfunctionandunderconditionsinwhichthelungisexposedtoenvironmentalstress.

AcknowledgmentsThisworkwassupportedbyNIHgrantR01HL66554,aHartFam-ilyEndowedChairinEmphysemaResearch,andtheBixlerCOPDFoundation.Thecritical readingof thismanuscriptbyMarkNicolls,StanfordMedicalSchool,isgratefullyacknowledged.

Addresscorrespondenceto:NorbertF.Voelkel,VictoriaJohnsonCenterforEmphysemaResearch,SchoolofMedicine,VirginiaCommonwealthUniversity,1101E.MarshallSt.SangerHall7024,Richmond,Virginia23298,USA.Phone:(804)628-9615;Fax:(804)628-0325;E-mail:[email protected].




1.Fulton,J.F.1930.Selected readings in the history of physiology.CharlesC.Thomas.Springfield,Illinois,USA.307315.

2.Snider,G.L.,Kleinerman,J.,Thurlbeck,W.M.,andBengali,Z.H.1985.Thedefinitionofemphysema.Am. Rev. Respir. Dis.132:182185.

3.Laennec,R.T.1819.De auscultation mdiate; ou, Trait du diagnostic del maladies des poumons et du coeur.Bros-sonetChaude.Paris,France.

4.Laennec,R.T.1834.A treatise on the diseases of the chest.Longman.London,UnitedKingdom.

5.Filley,G.F.1967.Emphysemaandchronicbronchi-tis:clinicalmanifestationsandtheirphysiologicsignificance.Med. Clin. North Am.51:283292.

6.Sahebjami,H.1992.Emphysema-likechangesinHIV.Ann. Intern. Med.116:876.

7.Tuder,R.M.,andVoelkel,N.F.2002.Thepatho-biologyof chronicbronchitis andemphysema.InChronic obstructive lung diseases. N.F.VoelkelandW.MacNee,editors.B.C.Decker.London,UnitedKingdom.90113.

8.Finkelstein,R.,etal.1995.Morphometryofsmallairwaysinsmokersanditsrelationshiptoemphy-sematypeandhyperresponsiveness.Am. J. Respir. Crit. Care Med.152:267276.

9.Cote,C.,Zilberberg,M.D.,Mody,S.H.,Dordelly,L.J.,andCelli,B.2007.HaemoglobinlevelanditsclinicalimpactinacohortofpatientswithCOPD.Eur. Respir. J.29:923929.

10.Engelen,M.P.,Schols,A.M.,Lamers,R.J.,andWout-ers,E.F.1999.Differentpatternsofchronictissuewastingamongpatientswithchronicobstructivepulmonarydisease.Clin. Nutr.18:275280.

11.Sabit,R.,etal.2007.Arterialstiffnessandosteo-porosisinchronicobstructivepulmonarydisease.Am. J. Respir. Crit. Care Med.175:12591265.

12.Celli,B.R.2006.Chronicobstructivepulmonarydisease: fromunjustifiednihilism to evidence-basedoptimism.Proc. Am. Thorac. Soc.3:5865.

13.Murray,C.J., andLopez,A.D.1997.Alternativeprojectionsofmortalityanddisabilitybycause19902020: Global Burden of Disease Study.Lancet.349:14981504.

14.Sullivan,S.D.,Ramsey,S.D.,andLee,T.A.2000.TheeconomicburdenofCOPD.Chest.117:5S9S.

15.Symposium of Emphysema and the ChronicBronchitisSyndrome.1959.Am. Rev. Respir. Dis. 80:1213.

16.Fletcher,C.,andPeto,R.1977.Thenaturalhistoryofchronicairflowobstruction.Br. Med. J.1:16451648.

17.Abbey,D.E.,etal.1998.Long-termparticulateandotherairpollutantsand lung function innon-smokers.Am. J. Respir. Crit. Care Med.158:289298.

18.Jimenez,L.A.,etal.2000.ActivationofNF-kappaBbyPM(10)occursviaaniron-mediatedmechanismintheabsenceof IkappaBdegradation.Toxicol. Appl. Pharmacol.166:101110.

19.Karakatsani,A.,etal.2003.Airpollutioninrelationtomanifestationsofchronicpulmonarydisease:anestedcase-controlstudyinAthens,Greece.Eur. J. Epidemiol.18:4553.

20.Joos,L.,Pare,P.D.,andSandford,A.J.2002.Geneticriskfactors.InChronic obstructive lung diseases.N.VoelkelandW.MacNee,editors.B.C.Decker.Lon-don,UnitedKingdom.5664.

21.Ferrarotti,I.,etal.2003.TumournecrosisfactorfamilygenesinaphenotypeofCOPDassociatedwithemphysema.Eur. Respir. J.21:444449.

22.Demeo,D.L.,etal.2006.TheSERPINE2geneisassociatedwithchronicobstructivepulmonarydisease.Am. J. Hum. Genet.78:253264.

23.Ito,I.,etal.2005.Matrixmetalloproteinase-9pro-moterpolymorphismassociatedwithupperlungdominantemphysema.Am. J. Respir. Crit. Care Med.172:13781382.

24.Gauldie,J.,etal.2006.Smad3signalinginvolvedinpulmonaryfibrosisandemphysema.Proc. Am. Thorac. Soc.3:696702.

25.Jankowich,M.D.,Polsky,M.,Klein,M.,andRounds,S.2007.Heterogeneity incombinedpulmonaryfibrosisandemphysema.Respiration.730:17.

26.Gross,P.,Babyak,M.A.,Tolker,E.,andKaschak,M. 1964. Enzymatically produced pulmonaryemphysema:apreliminaryreport.J. Occup. Med.6:481484.

27.Eriksson, S. 1964. Pulmonary emphysema andalpha1-antitrypsin deficiency.Acta Med. Scand.175:197205.

28.Agusti,A.,MacNee,W.,Donaldson,K.,andCosio,M.2003.Hypothesis:doesCOPDhaveanautoim-munecomponent?Thorax.58:832834.

29.Aoshiba,K.,Yokohori,N., andNagai,A. 2003.Alveolarwallapoptosiscauseslungdestructionandemphysematouschanges.Am. J. Respir. Cell Mol. Biol.28:555562.

30.Grumelli,S., etal.2004.Animmunebasisforlungparenchymaldestructioninchronicobstructivepul-monarydiseaseandemphysema.PLoS Med.1:e8.

31.Zhang,X.,Shan,P.,Jiang,G.,Cohn,L.,andLee,P.J.2006.Toll-likereceptor4deficiencycausespulmo-naryemphysema.J. Clin. Invest.116:30503059.

32.Morris,D.G.,andSheppard,D.2006.Pulmonaryemphysema:whenmoreisless.Physiology (Bethesda).21:396403.

33.Yoshida,T.,andTuder,R.M.2007.Pathobiologyofcigarettesmoke-inducedchronicobstructivepul-monarydisease.Physiol. Rev.87:10471082.

34.Calabrese,F.,etal.2005.Markedalveolarapoptosis/proliferationimbalanceinend-stageemphysema.Respir. Res.6:14.

35.Kanazawa,H.,andYoshikawa,J.2005.Elevatedoxidativestressandreciprocalreductionofvascu-larendothelialgrowthfactorlevelswithseverityofCOPD.Chest.128:31913197.

36.Tuder,R.M.,etal.2003.Oxidativestressandapop-tosisinteractandcauseemphysemaduetovascularendothelialgrowthfactorreceptorblockade.Am. J. Respir. Cell Mol. Biol.29:8897.

37.Vandivier,R.W.,Henson,P.M.,andDouglas,I.S.2006.Buryingthedead:theimpactoffailedapop-toticcellremoval(efferocytosis)onchronicinflam-matorylungdisease.Chest.129:16731682.

38.Nyunoya,T.,etal.2006.Cigarettesmokeinducescellular senescence.Am. J. Respir. Cell Mol. Biol.35:681688.

39.Tsuji,T.,Aoshiba,K.,andNagai,A.2006.Alveolarcellsenescenceinpatientswithpulmonaryemphysema.Am. J. Respir. Crit. Care Med.174:886893.

40.Taraseviciene-Stewart,L.,etal.2006.Isalveolardestructionandemphysemainchronicobstruc-tivepulmonarydiseaseanimmunedisease?Proc. Am. Thorac. Soc.3:687690.

41.Voelkel,N.F.2002.Historicaloverviewofemphy-sema.InChronic obstructive lung diseases.N.F.VoelkelandW.MacNee, editors.B.C.Decker.London,UnitedKingdom.16.

42.Hogg,J.C.,etal.2004.Thenatureofsmall-airwayobstructioninchronicobstructivepulmonarydisease.N. Engl. J. Med.350:26452653.

43.Mercer, B.A., Kolesnikova, N., Sonett, J., andDArmiento, J. 2004. Extracellular regulatedkinase/mitogenactivatedproteinkinase isup-regulatedinpulmonaryemphysemaandmediatesmatrixmetalloproteinase-1inductionbycigarettesmoke.J. Biol. Chem.279:1769017696.

44.Taraseviciene-Stewart,L.,etal.2005.Ananimalmodelofautoimmuneemphysema.Am. J. Respir. Crit. Care Med.171:734742.

45.Houghton,A.M.,etal.2006.Elastin fragmentsdrivediseaseprogression inamurinemodelofemphysema.J. Clin. Invest.116:753759.

46.Ofulue,A.F.,andKo,M.1999.Effectsofdepletionofneutrophilsormacrophagesondevelopmentofcigarettesmoke-inducedemphysema.Am. J. Physiol.277:L97L105.

47.Hautamaki,R.D.,Kobayashi,D.K.,Senior,R.M.,

andShapiro,S.D.1997.Requirementformacro-phageelastaseforcigarettesmoke-inducedemphy-semainmice.Science.277:20022004.

48.Eidelman,D.,etal.1990.Cellularityofthealveo-larwalls insmokersanditsrelationtoalveolardestruction. Functional implications.Am. Rev. Respir. Dis.141:15471552.

49.Finkelstein,R.,Fraser,R.S.,Ghezzo,H.,andCosio,M.G.1995.Alveolarinflammationanditsrelationtoemphysemainsmokers.Am. J. Respir. Crit. Care Med.152:16661672.

50.Owen,C.A.2005.Proteinasesandoxidantsastar-getsinthetreatmentofchronicobstructivepulmo-narydisease.Proc. Am. Thorac. Soc.2:373385.

51.Fischer,U.,Janicke,R.U.,andSchulze-Osthoff,K.2003.Manycutstoruin:acomprehensiveupdateofcaspasesubstrates.Cell Death Differ.10:76100.

52.Elkington,P.T.,andFriedland,J.S.2006.Matrixmetalloproteinases in destructive pulmonarypathology.Thorax.61:259266.

53.Greenlee,K.J.,Werb,Z.,andKheradmand,F.2007.Matrixmetalloproteinasesinlung:multiple,mul-tifarious,andmultifaceted.Physiol. Rev.87:6998.

54.DArmiento,J.,Dalal,S.S.,Okada,Y.,Berg,R.A.,andChada,K.1992.Collagenaseexpressioninthelungsoftransgenicmicecausespulmonaryemphysema.Cell.71:955961.

55.Foronjy,R.F.,Okada,Y.,Cole,R.,andDArmiento,J.2003.Progressiveadult-onsetemphysemaintrans-genicmiceexpressinghumanMMP-1inthelung.Am. J. Physiol. Lung Cell Mol. Physiol.284:L727L737.

56.Segura-Valdez,L., et al. 2000.UpregulationofgelatinasesAandB, collagenases1and2,andincreasedparenchymalcelldeathinCOPD.Chest.117:684694.

57.Stone,P.J.,etal.1995.Elastinandcollagendeg-radationproductsinurineofpatientswithcysticfibrosis.Am. J. Respir. Crit. Care Med.152:157162.

58.Wright,J.L.,andChurg,A.1995.Smoke-inducedemphysemainguineapigsisassociatedwithmor-phometricevidenceofcollagenbreakdownandrepair.Am. J. Physiol.268:L17L20.

59.Zheng,T.,etal.2005.RoleofcathepsinS-depen-dent epithelial cell apoptosis in IFN-gamma-induced alveolar remodeling and pulmonaryemphysema.J. Immunol.174:81068115.

60.Wang,B.,etal.2006.CathepsinScontrolsangio-genesis and tumor growth via matrix-derivedangiogenicfactors.J. Biol. Chem.281:60206029.

61.Demura,Y.,Taraseviciene-Stewart,L.,Scerbavicius,R.,Tuder,R.M.,andVoelkel,N.F.2004.N-acetyl-cysteinetreatmentprotectsagainstVEGF-receptorblockade-relatedemphysema.COPD.1:2532.

62.Kasahara,Y.,etal.2000.InhibitionofVEGFrecep-torscauseslungcellapoptosisandemphysema.J. Clin. Invest.106:13111319.

63.Petrache,I.,etal.2006.Anovelantiapoptoticroleforalpha1-antitrypsininthepreventionofpul-monaryemphysema.Am. J. Respir. Crit. Care Med.173:12221228.

64.Tuder,R.M.,Petrache,I.,Elias,J.A.,Voelkel,N.F.,andHenson,P.M.2003.Apoptosisandemphy-sema:themissinglink.Am. J. Respir. Cell Mol. Biol.28:551554.

65.Churg,A.,Wang,R.D.,Xie,C.,andWright, J.L.2003.alpha-1-Antitrypsinamelioratescigarettesmoke-inducedemphysemainthemouse.Am. J. Respir. Crit. Care Med.168:199207.

66.Petrache,I.,etal.2006.a-1Antitrypsininhibitscaspase-3activity,preventinglungendothelialcellapoptosis.Am. J. Pathol.169:11551166.

67.Lewis,E.C.,Shapiro,L.,Bowers,O.J.,andDinarel-lo,C.A.2005.Alpha1-antitrypsinmonotherapyprolongsisletallograftsurvivalinmice.Proc. Natl. Acad. Sci. U. S. A.102:1215312158.

68.Fujita,M.,etal.2001.Overexpressionoftumornecrosisfactor-alphaproducesanincreaseinlungvolumesandpulmonaryhypertension.Am. J. Physiol.




Lung Cell Mol. Physiol.280:L39L49. 69.Singh,A.,etal.2006.Glutathioneperoxidase2,the

majorcigarettesmoke-inducibleisoformofGPXinlungs,isregulatedbyNrf2.Am. J. Respir. Cell Mol. Biol.35:639650.

70.Rangasamy,T.,etal.2004.GeneticablationofNrf2enhancessusceptibilitytocigarettesmoke-inducedemphysemainmice.J. Clin. Invest.114:12481259.

71.Johnson,G.B.,Brunn,G.J.,Kodaira,Y.,andPlatt,J.L.2002.Receptor-mediatedmonitoringoftissuewell-beingviadetectionofsolubleheparansulfatebyToll-likereceptor4.J. Immunol.168:52335239.

72.Maes,T.,etal.2006.MurineTLR4isimplicatedincigarettesmoke-inducedpulmonaryinflammation.Int. Arch. Allergy Immunol.141:354368.

73.Petrache, I.,etal.2005.Ceramideupregulationcausespulmonarycellapoptosisandemphysema-likediseaseinmice.Nat. Med.11:491498.

74.Gebel,S.,etal.2006.Thekineticsoftranscriptomicchangesinducedbycigarettesmokeinratlungsrevealsaspecificprogramofdefense,inflamma-tion,andcircadianclockgeneexpression.Toxicol. Sci.93:422431.

75.Pisetsky,D.S.2007.Theroleofnuclearmacromol-eculesininnateimmunity.Proc. Am. Thorac. Soc.4:258262.

76.Mahoney,J.A.,andRosen,A.2005.Apoptosisandautoimmunity.Curr. Opin. Immunol.17:583588.

77.Sullivan,A.K.,etal.2005.OligoclonalCD4+Tcellsinthelungsofpatientswithsevereemphysema.Am. J. Respir. Crit. Care Med.172:590596.

78.Koethe,S.M.,Kuhnmuench,J.R.,andBecker,C.G.2000.Neutrophilprimingbycigarettesmokecon-densateandatobaccoanti-idiotypicantibody.Am. J. Pathol.157:17351743.

79.Lee,S.H.,etal.2007.Antielastinautoimmunityintobaccosmoking-inducedemphysema.Nat. Med.13:567569.

80.Wei,Y.Q.,etal.2000.Immunotherapyoftumorswithxenogeneicendothelialcellsasavaccine.Nat. Med.6:11601166.

81.Taraseviciene-Stewart,L.,etal.2006.Isalveolardestructionandemphysemainchronicobstruc-tivepulmonarydiseaseanimmunedisease?Proc. Am. Thorac. Soc.3:687690.

82.Robbins,C.S.,etal.2004.Cigarettesmokedecreas-espulmonarydendriticcellsandimpactsantiviralimmuneresponsiveness.Am. J. Respir. Cell Mol. Biol.30:202211.

83.Soler,P.,Moreau,A.,Basset,F.,andHance,A.J.1989.Cigarettesmoking-inducedchangesinthenumber anddifferentiated stateofpulmonarydendriticcells/Langerhanscells.Am. Rev. Respir. Dis.139:11121117.

84.Rose,N.R.,andBona,C.1993.Definingcriteriaforautoimmunediseases(Witebskyspostulatesrevisited).Immunol. Today.14:426430.

85.Peene,I.,etal.2004.Historyanddiagnosticvalueofantibodies tocitrullinatedproteins in rheu-matoidarthritis.Int. J. Immunopathol. Pharmacol.17:107116.

86.Hunt,D.P.,etal.2006.Pulmonarycapillaritisanditsrelationshiptodevelopmentofemphysemainhypocomplementaemicurticarialvasculitissyn-drome.Sarcoidosis Vasc. Diffuse Lung Dis.23:7072.

87.Ma,B.,etal.2006.Adenosinemetabolismandmurinestrain-specificIL-4-inducedinflamma-tion, emphysema, and fibrosis. J. Clin. Invest.116:12741283.

88.Blackburn,M.R., et al. 2000.Metabolic conse-

quencesofadenosinedeaminasedeficiencyinmiceareassociatedwithdefectsinalveogenesis,pulmo-naryinflammation,andairwayobstruction.J. Exp. Med.192:159170.

89.Harrington,E.O., Smeglin,A., Parks,N.,New-ton,J.,andRounds,S.2000.Adenosineinducesendothelialapoptosisbyactivatingproteintyro-sinephosphatase:apossibleroleofp38alpha.Am. J. Physiol. Lung Cell Mol. Physiol.279:L733L742.

90.Jeffery, P.K. 1999.Differences and similaritiesbetweenchronicobstructivepulmonarydiseaseandasthma.Clin. Exp. Allergy.29(Suppl.2):1426.

91.Hodge,S.,Hodge,G.,Holmes,M.,andReynolds,P.N.2005.IncreasedairwayepithelialandT-cellapoptosisinCOPDremainsdespitesmokingces-sation.Eur. Respir. J.25:447454.

92.Kasahara,Y.,etal.2001.Endothelialcelldeathanddecreasedexpressionofvascularendothelialgrowthfactorandvascularendothelialgrowthfac-torreceptor2inemphysema.Am. J. Respir. Crit. Care Med.163:737744.

93.Zhong,C.Y.,Zhou,Y.M.,Joad,J.P.,andPinkerton,K.E. 2006.Environmental tobacco smoke sup-pressesnuclearfactor-kappaBsignalingtoincreaseapoptosisininfantmonkeylungs.Am. J. Respir. Crit. Care Med.174:428436.

94.Liebow,A.A.1959.Pulmonaryemphysemawithspecialreferencetovascularchanges.Am. Rev. Respir. Dis.80:6793.

95.Santos,S.,etal.2002.Characterizationofpulmo-naryvascularremodellinginsmokersandpatientswithmildCOPD.Eur. Respir. J.19:632638.

96.Shapiro,S.D.2000.VascularatrophyandVEGFR-2signaling:oldtheoriesofpulmonaryemphysemameetnewdata.J. Clin. Invest.106:13091310.

97.Voelkel,N.,andTaraseviciene-Stewart,L.2005.Emphysema: anautoimmunevasculardisease?Proc. Am. Thorac. Soc.2:2325.

98.Wright,J.L.,Tai,H.,andChurg,A.2006.Vasoac-tivemediatorsandpulmonaryhypertensionaftercigarettesmokeexposureintheguineapig.J. Appl. Physiol.100:672678.

99.Yamato,H.,Sun,J.P.,Churg,A.,andWright,J.L.1996.Cigarette smoke-induced emphysema inguineapigsisassociatedwithdiffuselydecreasedcapillary density and capillarynarrowing.Lab. Invest.75:211219.

100.Voelkel,N.F.,Vandivier,R.W.,andTuder,R.M.2006.Vascularendothelialgrowthfactorinthelung.Am. J. Physiol. Lung Cell Mol. Physiol.290:L209L221.

101.Fehrenbach,H.,Kasper,M.,Haase,M.,Schuh,D.,andMuller,M.1999.Differentialimmunolocaliza-tionofVEGFinratandhumanadultlung,andinexperimentalratlungfibrosis:light,fluorescence,andelectronmicroscopy.Anat. Rec.254:6173.

102.Tang,K.,Rossiter,H.B.,Wagner,P.D.,andBreen,E.C.2004.Lung-targetedVEGFinactivationleadstoanemphysemaphenotypeinmice.J. Appl. Physiol.97:15591566.

103.Lammert,E.,etal.2003.RoleofVEGF-Ainvascular-izationofpancreaticislets.Curr. Biol.13:10701074.

104.Eremina,V.,etal.2006.Vascularendothelialgrowthfactorasignalinginthepodocyte-endothelialcom-partmentisrequiredformesangialcellmigrationandsurvival.J. Am. Soc. Nephrol.17:724735.

105.Lee,S., et al. 2007.AutocrineVEGF signaling isrequiredforvascularhomeostasis.Cell.130:691703.

106.Stevens,T.,Kasper,M.,Cool,C.,andVoelkel,N.2005. Pulmonary circulation and pulmonaryhypertension.InEndothelial cells in health and disease.

W.C.Aird,editor.Taylor&FrancisGroup.BocaRaton,Florida,USA.417438.

107.Nana-Sinkam, P.S., et al. 2007. Prostacyclinpreventspulmonary endothelial cell apoptosisinducedbycigarettesmoke.Am. J. Respir. Crit. Care Med.175:676685.

108.Ziel, K.A., et al. 2005. Oxidants in signaltransduction:impactonDNAintegrityandgeneexpression.FASEB J.19:387394.

109.Golpon,H.A.,etal.2004.Emphysemalungtissuegeneexpressionprofiling.Am. J. Respir. Cell Mol. Biol.31:595600.

110.Takahashi,A.,etal.2006.Mitogenicsignallingandthep16INK4a-Rbpathwaycooperatetoenforceirreversible cellular senescence. Nat. Cell Biol.8:12911297.

111.Sato,T.,etal.2006.Senescencemarkerprotein-30protectsmicelungsfromoxidativestress,aging,andsmoking.Am. J. Respir. Crit Care Med.174:530537.

112.Massaro,D.,Massaro,G.D.,Baras,A.,Hoffman,E.P.,andClerch,L.B.2004.Calorie-relatedrapidonsetofalveolarloss,regeneration,andchangesinmouselunggeneexpression.Am. J. Physiol Lung Cell Mol. Physiol.286:L896L906.

113.Thet,L.A.,Delaney,M.D.,Gregorio,C.A.,andMas-saro,D.1977.Proteinmetabolismby rat lung:influenceoffasting,glucose,andinsulin.J. Appl. Physiol.43:463467.

114.Coxson,H.O., et al. 2004.Early emphysema inpatientswithanorexianervosa.Am. J. Respir. Crit. Care Med.170:748752.

115.Shifren,A.,andMecham,R.P.2006.Thestumblingblockinlungrepairofemphysema:elasticfiberassembly.Proc. Am. Thorac. Soc.3:428433.

116.Tanaka,N.,Tajima,S.,Ishibashi,A.,Uchida,K.,andShigematsu,T.2001.Immunohistochemicaldetec-tionoflipidperoxidationproducts,protein-boundacroleinand4-hydroxynonenalproteinadducts,inactinicelastosisofphotodamagedskin.Arch. Dermatol. Res.293:363367.

117.Wu,C.C.,etal.2006.Upregulationofendothelialhemeoxygenase-1expressionthroughtheactivationoftheJNKpathwaybysublethalconcentrationsofacrolein.Toxicol. Appl. Pharmacol.214:244252.

118.Fujioka,K.,andShibamoto,T.2006.Determina-tionof toxic carbonyl compounds in cigarettesmoke.Environ. Toxicol.21:4754.

119.Uchida,K.,etal.1998.Protein-boundacrolein:potentialmarkersforoxidativestress.Proc. Natl. Acad. Sci. U. S. A.95:48824887.

120.Ito,K.,etal.2005.Decreasedhistonedeacetylaseactivityinchronicobstructivepulmonarydisease.N. Engl. J. Med.352:19671976.

121.Szulakowski,P.,etal.2006.Theeffectofsmokingonthetranscriptionalregulationoflunginflamma-tioninpatientswithchronicobstructivepulmonarydisease.Am. J. Respir. Crit. Care Med.174:4150.

122.Suratt,B.T.,etal.2003.Humanpulmonarychime-rismafterhematopoieticstemcelltransplantation.Am. J. Respir. Crit. Care Med.168:318322.

123.Bonsignore,M.R.,etal.2006.CirculatingCD34+cellsaredecreasedinchronicobstructivepulmo-narydisease.Proc. Am. Thorac. Soc.3:537538.

124.Hattori, K., et al. 2001. Vascular endothelialgrowthfactorandangiopoietin-1stimulatepost-natalhematopoiesisbyrecruitmentofvasculo-genicandhematopoieticstemcells.J. Exp. Med.193:10051014.

125.Kotton,D.N.,andFine,A.2008.Lungstemcells.Cell Tissue Res.331:145156.


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Emphysema Patofisiologi 2