纳米缓释型CO供体SMA-CORM2通过调控巨噬细胞重编程缓解博来霉素诱导的肺纤维化

纳米缓释型CO供体SMA-CORM2通过调控巨噬细胞重编程缓解博来霉素诱导的肺纤维化摘要：

博来霉素（Bleomycin，BLM）是一种临床广泛应用的化疗药物，主要用于肺癌、淋巴瘤等恶性肿瘤的治疗。然而，它也会导致肺纤维化（Pulmonaryfibrosis，PF）的发生，其具体机制尚不清楚。本研究旨在评估纳米缓释型CO供体SMA/CORM2（SMA/CORM2）通过调节巨噬细胞（Macrophage，Mφ）重编程的作用是否可以缓解BLM诱导的PF。

我们通过对小鼠进行肺损伤模型的建立，得出了以下结果：SMA/CORM2治疗组相较于对照组，能够显著减轻BLM诱导的肺纤维化症状，包括肺组织的非正常增生、纤维化和肺功能障碍。同时，我们发现在SMA/CORM2治疗组中，膜结合型TGF-βRII（membrane-boundTGF-βRII）的表达显著下调，同时M1型巨噬细胞的数量增加，M2型巨噬细胞的数量减少。此外，SMA/CORM2还能够下调转录因子RUNX1T1的表达。

这项研究表明，SMA/CORM2可以通过调节Mφ的重编程，抑制BLM诱导的PF的发生。这一作用可能涉及到membrane-boundTGF-βRII、M1型和M2型巨噬细胞的平衡，以及RUNX1T1的抑制。这些发现可以为临床治疗PF提供新思路。

关键词：纳米缓释型CO供体，博来霉素，肺纤维化，巨噬细胞，重编程

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