納米緩釋型CO供體SMA-CORM2通過調(diào)控巨噬細胞重編程緩解博來霉素誘導的肺纖維化

納米緩釋型CO供體SMA-CORM2通過調(diào)控巨噬細胞重編程緩解博來霉素誘導的肺纖維化摘要：

博來霉素（Bleomycin，BLM）是一種臨床廣泛應用的化療藥物，主要用于肺癌、淋巴瘤等惡性腫瘤的治療。然而，它也會導致肺纖維化（Pulmonaryfibrosis，PF）的發(fā)生，其具體機制尚不清楚。本研究旨在評估納米緩釋型CO供體SMA/CORM2（SMA/CORM2）通過調(diào)節(jié)巨噬細胞（Macrophage，Mφ）重編程的作用是否可以緩解BLM誘導的PF。

我們通過對小鼠進行肺損傷模型的建立，得出了以下結(jié)果：SMA/CORM2治療組相較于對照組，能夠顯著減輕BLM誘導的肺纖維化癥狀，包括肺組織的非正常增生、纖維化和肺功能障礙。同時，我們發(fā)現(xiàn)在SMA/CORM2治療組中，膜結(jié)合型TGF-βRII（membrane-boundTGF-βRII）的表達顯著下調(diào)，同時M1型巨噬細胞的數(shù)量增加，M2型巨噬細胞的數(shù)量減少。此外，SMA/CORM2還能夠下調(diào)轉(zhuǎn)錄因子RUNX1T1的表達。

這項研究表明，SMA/CORM2可以通過調(diào)節(jié)Mφ的重編程，抑制BLM誘導的PF的發(fā)生。這一作用可能涉及到membrane-boundTGF-βRII、M1型和M2型巨噬細胞的平衡，以及RUNX1T1的抑制。這些發(fā)現(xiàn)可以為臨床治療PF提供新思路。

關(guān)鍵詞：納米緩釋型CO供體，博來霉素，肺纖維化，巨噬細胞，重編程

Abstract:

Bleomycin(BLM)isawidelyusedchemotherapydrugforthetreatmentofmalignanttumorssuchaslungcancerandlymphoma.However,itcanalsocausepulmonaryfibrosis(PF),andthespecificmechanismisstillunclear.Thisstudyaimstoevaluatetheeffectofnano-sustainedreleaseCOdonorSMA/CORM2(SMA/CORM2)onalleviatingBLM-inducedPFbyregulatingmacrophage(Mφ)reprogramming.

Byestablishingamouselunginjurymodel,wefoundthattheSMA/CORM2treatmentgroupcansignificantlyalleviatethesymptomsofBLM-inducedPFcomparedwiththecontrolgroup,includingabnormalproliferation,fibrosisoflungtissue,andlungdysfunction.Atthesametime,wefoundthattheexpressionofthemembrane-boundTGF-βRIIwassignificantlydown-regulatedintheSMA/CORM2treatmentgroup,whilethenumberofM1macrophagesincreasedandthenumberofM2macrophagesdecreased.Inaddition,SMA/CORM2canalsodown-regulatetheexpressionofthetranscriptionfactorRUNX1T1.

ThisstudysuggeststhatSMA/CORM2caninhibittheoccurrenceofBLM-inducedPFbyregulatingMφreprogramming.Thiseffectmayinvolvethebalanceofmembrane-boundTGF-βRII,M1andM2macrophages,andtheinhibitionofRUNX1T1.ThesefindingsmayprovidenewideasforclinicaltreatmentofPF.

Keywords:nano-sustainedreleaseCOdonor,bleomycin,pulmonaryfibrosis,macrophages,reprogrammingPulmonaryfibrosis(PF)isaprogressiveandirreversiblediseasecharacterizedbyexcessivedepositionofextracellularmatrixandfibrotictissueinthelungs.Itisacomplexdiseasewithmultifactorialcauses,includingenvironmentalexposures,geneticsusceptibility,andimmunedysregulation.CurrenttherapiesforPFfocusonsuppressinginflammationandfibrosis,buttheyareoftenineffectiveandassociatedwithsignificantsideeffects.

Inrecentyears,thereprogrammingofmacrophageshasemergedasapotentialtherapeuticstrategyforPF.Macrophagesareakeycomponentoftheimmunesystemandplayacriticalroleintheinitiationandresolutionofinflammation.InPF,macrophagesareactivatedandpolarizedtowardsapro-fibroticphenotype,whichpromotesthedevelopmentoffibrosis.Therefore,reprogrammingmacrophagestowardsananti-fibroticphenotypemaybeapromisingtherapeuticapproach.

Inthisstudy,theresearchersusedanano-sustainedreleasecarbonmonoxide(CO)donor,SMA/CORM2,totreatmicewithbleomycin-inducedPF.SMA/CORM2isaCO-releasingmoleculethathasbeenshowntohaveanti-inflammatoryandanti-fibroticeffectsinvariousmodelsofdisease.TheresearchersfoundthattreatmentwithSMA/CORM2significantlyreducedlungfibrosisandimprovedlungfunctioninthemice.

FurtheranalysisrevealedthatthebeneficialeffectsofSMA/CORM2wereassociatedwiththereprogrammingofmacrophages.TreatmentwithSMA/CORM2increasedtheexpressionofmembrane-boundTGF-βRII,areceptorthatisinvolvedintheactivationofanti-fibroticsignalingpathways.Italsoshiftedthebalanceofmacrophagesubtypesfrompro-inflammatoryM1toanti-inflammatoryM2macrophages.Finally,SMA/CORM2down-regulatedtheexpressionofthetranscriptionfactorRUNX1T1,whichisknowntobeinvolvedinmacrophagepolarizationtowardsapro-fibroticphenotype.

Overall,thisstudyprovidesevidencethatSMA/CORM2caninhibitthedevelopmentofPFbyreprogrammingmacrophagestowardsananti-fibroticphenotype.ThesefindingssuggestthattargetingmacrophagereprogrammingmaybeapromisingtherapeuticapproachforPF.However,furtherstudiesareneededtoconfirmtheefficacyandsafetyofSMA/CORM2inhumanpatientswithPFInadditiontotargetingmacrophagereprogramming,otherpotentialtherapeuticapproachesforPFhavebeeninvestigated.Forexample,antifibroticdrugssuchaspirfenidoneandnintedanibhavebeenapprovedforuseinpatientswithidiopathicpulmonaryfibrosis.Thesedrugshavebeenshowntoinhibitfibroblastproliferationandextracellularmatrixdeposition,andimprovelungfunctionandqualityoflifeinpatientswithPF.

OtherpotentialtherapeutictargetsforPFincludeimmunecellrecruitmentandactivation,mechanotransduction,andepithelial-mesenchymaltransition.Forexample,arecentstudydemonstratedthatinhibitingtherecruitmentofmonocytestothelungcouldattenuatePFdevelopmentinmice,highlightingtheimportanceofimmunecellinvolvementinthepathogenesisofPF.

FurtherresearchintothesepotentialtherapeutictargetsmayleadtothedevelopmentofnoveltreatmentsforPF.Theuseofanimalmodelssuchasthebleomycin-inducedPFmodelandtheTGF-β1-inducedPFmodelmayaidinthediscoveryanddevelopmentofnewtherapiesforPF.

Inconclusion,PFisacomplexanddebilitatingdiseasewithlimitedtreatmentoptions.TheinvolvementofmacrophagesinthepathogenesisofPFhighlightstheirpotentialasatherapeutictarget.Thereprogrammingofmacrophagestowardsananti-fibroticphenotypebySMA/CORM2providesapromisingapproachforthetreatmentofPF.FurtherresearchisneededtoevaluatethesafetyandefficacyofthisapproachinhumanpatientswithPF,andtoinvestigateotherpotentialtherapeutictargetsforthisdevastatingdiseaseDespitesignificantadvancesinourunderstandingofthepathogenesisofpulmonaryfibrosis(PF),therearestilllimitedtreatmentoptionsavailableforpatientswiththisdebilitatingdisease.Onepromisingavenueofresearchinvolvestargetingmacrophages,whicharecellsthatplayakeyroleinthedevelopmentandprogressionofPF.

Macrophagesareatypeofimmunecellthatareinvolvedinarangeofphysiologicalprocesses,includingwoundhealing,immunedefense,andtissueremodeling.InthecontextofPF,macrophagesarethoughttocontributetofibrosisbypromotinginflammationandtheactivationoffibroblasts,cellsthatproduceexcessconnectivetissueinthelungs.StudieshaveshownthatmacrophagesinthelungsofpatientswithPFhaveapro-fibroticphenotype,characterizedbyhighlevelsofcytokinesandgrowthfactorsthatstimulatefibroblastactivity.

Giventhisevidence,researchershaveinvestigatedwhetherreprogrammingmacrophagestowardsananti-fibroticphenotypecouldbeaviableapproachfortreatingPF.Onestrategyforachievingthisreprogramminginvolvestheuseofsmallmoleculeactivatorsofaproteincalledhemeoxygenase-1(HO-1),whichhasbeenshowntohaveanti-inflammatoryandanti-fibroticeffects.

Onesuchsmallmoleculeiscarbonmonoxide-releasingmolecule2(CORM2),whichisacompoundthatreleasescontrolledamountsofcarbonmonoxide(CO)inthebody.COisagasthatisnormallythoughtofasatoxicpollutant,butithasalsobeenshowntohaveanti-inflammatoryandanti-fibroticproperties.StudieshaveshownthattreatmentwithCORM2caninduceashiftinmacrophagephenotypefrompro-fibrotictoanti-fibrotic,resultinginreducedinflammationandfibrosisinanimalmodelsofPF.

Anotherapproachforreprogrammingmacrophagesinvolvestheuseofsmallmoleculeactivatorsofthepparγpathway,whichisasignalingpathwayinvolvedinregulatinginflammationandfibrosis.Onesuchactivatorispioglitazone,whichisadrugthatiscommonlyusedtotreattype2diabetes.Pioglitazon