皮肤的屏障作用英文文献

1、MoisturizationandskinbarrierfunctionABSTRACT:Overthepastdecadegreatprogresshasbeenmadetowardelucidatingthestructureandfunctionofthestratumcorneum(SC),theoutermostlayeroftheepidermis.SCcells(corneocytes)protectagainstdesiccationandenvironmentalbytheSCislargelydependentonseveralfactors.First,intercell

2、ularlamellarlipids,organizedpredominantlyinanorthorhombicgelphase,provideaneffectivebarriertothepassageofwaterthroughthetissue.Secondly,thediffusionpathlengthalsoretardswaterloss,sincewatermusttraversethetortuouspathcreatedbytheSClayersandcorneocyteenvelopes.Thirdly,andequallyimportant,isnaturalmois

3、turizingfactor(NMF),acomplexmixtureoflow-molecular-weight,water-solublecompoundsfirstformedwithintheecorneocytesbydegradationofthehistidine-richproteinknownasfilaggrin.Eachmaturationstepleadingtotheformationofaneffectivemoisturebarrierincludingcorneocytestrengthening,lipidprocessing,andNMFgeneration

4、isinfluencedbythelevelofSChydration.Theseprocesses,aswellasthefinalstepofcorneodesmolysisthatmediatesexfoliations,areoftendisturbeduponenvironmentalchallenge,resultingindry,flakyskinconditions.ThepresentpaperreviewsourcurrentunderstandingofthebiologyoftheSC,particularlyitshomeostaticmechanismsofhydr

5、ation.Keywords:corneocyte,corneodesmolysis,filaggrin,naturalmoisturizingfactor,stratumcorneum.IntroductionForhumanstosurviveinaterrestrialenvironment,thelossofwaterfromtheskinmustbecarefullyregulatedbytheepidermis,afunctiondependentonthecomplexnatureofitsouterlayer,thestratumcorneum(SC)(1)。TheSCisas

6、electivelypermeable,heterogeneous,compositeouterlayeroftheepidermisthatprotectsagainstdesiccationandenvironmentalchallenge,andretainssufficientwatertoallowittofunctioninaridenvironments.ThesmallamountofwaterlossthatdoesoccurhydratestheouterlayersoftheSC,maintainingitsflexibilityandfacilitatingtheenz

7、ymaticreactionsthatdrivetheSCsmaturation(24).Thewater-retainingcapacityoftheSCishighlydependentuponthephenotypeofthecorneocytes,theirspatialarrangement,theprecisecompositionandphysicalpackingofextracellularlipids,andthepresenceofhighlyhygroscopiccompoundsfoundlargelywithinthecorneocytes(Fig.1).Under

8、conditionsofnormalhumidity(80%),asteepwatergradientexistsintheSC,whichcanbeviewedbyavarietyofeleganttechniques(Fig.2)(5,6).Thegradientisestablished,inpart,byadiscontinuityinthewater-bindingcapacitiesbetweendifferentcorneocytecelllayers,asdemonstratedviacryo-scanningelectronmicroscopy(Fig.3).Brie?y,c

9、orneocytesdonotappeartobeswollenatlowhydrationlevels(18-26%w/w),suggestingthatonlyboundwaterispresentintheSC.However,athigherhydrationlevels(57-87%w/w),thecorneocytesaremoreswolleninthecentralportionoftheSCcomparedwiththesuper?cialanddeeperlayers.Thecorneocytecellthicknessisshowntoincreaselinearlyin

10、adirectionperpendiculartotheskinsurfacewithincreasinghydration.Extracellularpoolsofwaterareonlyobservedatveryhighhydrationlevels(300%w/w).TheexplanationofthesedifferentialhydrationlevelsisrootedinthemechanismsinvolvedinSCmoisturization.Thepresentreviewdescribesthemostrecentresearchthatrevealsthecomp

11、lexityandintricacyoftheeverydayfunctioningoftheSCtomaintainhydrationinrelationtoever-changingenvironmentalconditions.Itshowsthatskinisinvolvedinaconstantbattletomaintainoptimalmoisturebarrierandprotectivefunctions.Asdiscussedthroughoutthissupplement,differentelementsoffundamentalskincareexercisedasa

12、dailyroutinetrulyhelptheskintoachieveitshealthieststate.StratumcorneummoisturizationatthemolecularlevelStratumcorneumTheSCconsistsofterminallydifferentiatedkeratinocytes(corneocytes)andthesecretedcontentsoflamellarbodies(2,8).Eachcorneocyteoriginatesfromanactivelyproliferatingkeratinocyteintheepider

13、misbeneaththeSC.Corneocyteproteinsaregenerallysequesteredtothecytosol,whileceramidesandotherlipidsareenrichedintheextracellularspace,wheretheyformacontinuousphase(8).Thephysicalpackingofthecorneocytescreatesatortuouspathformoleculestotraverse,effectivelyincreasingthediffusionlengthandtherebyimprovin

14、gtheSCbarrierfunction.Extracellularlipids,tightlyarrangedasacovalentlyboundmatrixinacrystallinephasecalledanorthorhombicpackingstatefurtherreducetherateofwater?uxthroughthetissue(9).Theconstitution,andthustheeffectiveness,ofthelipidbarrieraredependentontheabsoluteconcentrationsandtherelativeproporti

15、onsofthedifferentlipids(e.g.,ceramides,cholesterol,andfattyacids).LectinsanddesmosomesfoundintheSCalsohelptomaintainthestructuralcohesivenessoftheSC.Thereductionofwater?uxandlossthroughthetissueisnotthesolecauseoftheapparentdiscontinuityinhydrationbetweendifferentcorneocytelayers,however.Selectivere

16、tentionofwaterisrequiredaswell,centraltowhichisSCnaturalmoisturizingfactor(NMF).NaturalmoisturizingfactorFoundexclusivelyintheSC,NMFconsistsprimarilyofaminoacidsortheirderivatives,suchaspyrrolidonecarboxylicacid(PCA)andurocanicacid,togetherwithlacticacid,urea,citrate,andsugars(10)(Table1).Naturalmoi

17、sturizingfactorcompoundsarepresentinhighconcentrationswithincorneocytesandrepresentupto20W0%ofthedryweightoftheSC(11).Byabsorbingatmosphericwateranddissolvingintheirownwaterofhydration,hygroscopicNMFcomponentsactasveryef?cienthumectants(2).Biologically,thishumectancyallowstheoutermostlayersoftheSCto

18、remainhydrateddespitethedesiccatingactionoftheenvironment.CorneocytesthatpossessthehighestconcentrationofNMFretainmorewaterandappearmoreswollenwhenviewedundercryo-scanningelectronmicroscopy(7).However,NMFismuchmoreimportantthanthis.AsourunderstandingoftheterminaldifferentiationandSCmaturationprocess

19、hasincreased,ithasbecomeclearthat,bymaintainingfreewaterintheSC,NMFalsofacilitatescriticalbiochemicalevents.ThemoststrikingexampleofthisistheregulationofseveralcorneocyteproteasesthatareultimatelyresponsiblefortheverygenerationofNMFitself.OriginofNMF.ThecomponentsofNMFarederivedfrom?laggrin,a37-kDaS

20、Cproteininitiallysynthesizedinkeratohyalingranulesoftheepidermisaspro?laggrin,alarge(500kDa),highlybasic,heavilyphosphorylated,histidinerichprotein(2,12T5)(Fig.4).FirstexpressedinthegranularlayeroftheSCduringthe?nalstagesofepidermaldifferentiation,pro?laggrinconsistsofmultiple?laggrinrepeats(1012inh

21、umans)joinedbyshorthydrophobiclinkerpeptides(15).Extensivephosphorylationofinternalserineresiduesrenderspro?laggrinextremelyinsoluble.Pro?laggrinis,ineffect,synthesizedandthenprecipitatedwithinthekeratohyalingranuleasaninsoluble,osmoticallyinactiveprecursorofNMF.Duringthetransitionofthematuregranula

22、rcellintothecorneocyte,pro?laggrinisrapidlydephosphorylatedtoform?laggrin,atransientcomponentthatdoesnotpersistbeyondthetwotothreedeepestlayersoftheSC(16).AscorneocytematurationandprogressionthroughtheupwardlayersoftheSCproceeds,thecompleteproteolysisof?laggringeneratesNMF.Thetimingoftheentireproces

23、siscontrolled,inpart,bytheassociationof?laggrinwithkeratin,whichisthoughttoshield?laggrinfromprematureproteolysis(15).Althoughtheproteasescatalyzing?laggrinbreakdownintheSCremaintobeidenti?ed,thesignalIIthatinitializestheproteolysisde?nedstageofSCmaturationwasfoundtobethewatergradientwithintheSCitse

24、lf(17).FilaggrinsrelativelyshortlifespanisdependertherturnovertimeoftheSC.TheproteaseactivitythatresultsinthesuddenreleaseofaconcentratedNMFpoolisdelayeduntilthecorneocyteshave?attened,movedfarenoughoutintothedryerareasoftheSC,andthecorni?edcellenvelopeshavestrengthened.Oncetheseconditionshavebeenme

25、t,theSCcanwithstandtheresultingosmoticeffectsofNMFgeneration(15).OtherNMFcomponentsthatmaybeextracellulartothecorneocytesincludesugars,hyaluronicacid,urea,andespeciallylactate(18).Sincelactateisderivedfromeccrinesweat,itsgradientisdifferentfromtheamino-acid-derivedNMFcomponents(6).Age-relateddecline

26、inNMF.Thereisasigni?cantage-relateddeclineinthelevelofNMF.Electronmicroscopystudiesshowdecreasednumbersofkeratohyalingranulesinsenilexerosis(19);thissuggeststhattheintrinsicallylowerlevelsofNMFpresentinagedskin,comparedwiththelevelsinyoungskin,re?ectagenerallyreducedsynthesisofpro?laggrin.Furthermor

27、e,itislikelythatthelossofNMFisexacerbatedbytheage-relateddeclineinbarrierfunction(20).ThedeclineinNMFproductionprobablyre?ectsthecumulativeeffectsofactinicdamagesinceitwasobservedinSCrecoveredfromthebackofthehand(photodamaged),butnotfromtheinneraspectofthebiceps(photo-protected).Typicalpro?lesofSCde

28、pthversusNMFconcentration(obtainedbysequentialtapestrippingofelderlyindividuals)showadeclinetowardthesurfaceoftheskinofelderlysubjectscomparedtoyoungindividuals(2).Thisistypicalofnormalskinexposedtoroutinesoapwashing,duringwhichmuchofthereadilysolubleNMFiswashedoutofthesuper?cialSC(21).Indeed,recent

29、resultsfrominvivoconfocalmethodshavedemonstratedreductionsintheamountofallNMFaminoacidsinthesuper?ciallayersoftheSC(6),largelyasaresultofdamagefrombathingorultravioletlight.Improvementsincorneodesmolysisarenecessarytorapidlyalleviatethescalingand?akingassociatedwiththiscondition.Structuralchangesinc

30、orneocyteenvelopesDryskinisfurthercharacterizedbystructuralchangesincorneocyteenvelopes(CE)thatarearesultofreducedtransglutaminaseactivity.Thisbifunctionalenzymetransformsasoftorfragilecorneocyteenvelope(CEf)intoarigidcorneocyteenvelope(CEr)bymediatingthegamma-glutamyllysinecrosslinkingofspecialized

31、corneocyteproteins,andinaddition,theesteri?cationofceramidesandfattyacidstothecorni?edenvelope(22).Fragilecorneocyteenvelopespredominateindryskin.In?uenceofexternalhumidityonbarrierfunctionTheprocessesinvolvedinthemaintenanceofSChydrationappeartobeundertheprofoundin?uenceofexternalhumidity.Dendaandc

32、olleagues(23)analyzedcutaneousbarrierfunction,epidermalmorphology,andlipidcontentoftheSCinhairlessmicemaintainedfor2weeksinhighrelativehumidity(RH80%)andlowrelativehumidity(RH80%)toadryenvironment(RH10%),ascomparedtomicetransferredfromanormalenvironment(RH=4020%)toadryenvironment.Furthermore,thefree

33、aminoacidcontentintheSC,whilereduced24hafterthemicehadbeentransferredfromanormaltoadrycondition,recoveredtotheoriginallevelwithin3days.Bycontrast,micetransferredfromahumidtoadryconditionshowedasigni?cantlyloweraminoacidcontenteven7daysafterthetransfer.Theimmunoreactivityof?laggrinbecamefaintintheepi

34、dermisofthemicetransferredfromahumidornormaltoadryenvironment.Takentogether,theresultssuggestthatadrasticdecreaseintheenvironmentalhumidityreducestotalfreeaminoacidgeneration(andthusthelevelofNMFandthecapacityoftheSCtomaintainhydration),andconsequently,inducesskinsurfacedrynessintheSC.Inadditiontomo

35、dulatingthepro?laggrin?laggrinsystem,thewatercontentoftheSCalsoregulatesdesquamation(28)Theactionofspeci?chydrolasesintheSCthatdegradetheglycoproteincomplexesofcorneodesmosomesfacilitatescelllossfromthesurfaceoftheskin(8).AsdemonstratedbyRawlingsandcolleagues(29),desmosomaldegradationissigni?cantlyr

36、educedatlowrelativehumidity(RH=10%).Thesub-optimalwaterlevelintheSCmayinhibitSChydrolaseactivityand,thereby,suppressdesquamation(28).Giventherolethatenvironmentalhumidityplaysinin?uencingepidermalstructureandfunction,lowhumidityiswidelythoughttoinduceorexacerbatevariouscutaneousdisorders.Forexample,xerosisandothercommondryskinconditionsarecharacterized,i