骨髓間充質(zhì)干細(xì)胞移植防治失血性休克大鼠肺損傷的作用及機(jī)制

骨髓間充質(zhì)干細(xì)胞移植防治失血性休克大鼠肺損傷的作用及機(jī)制摘要：目的：探究骨髓間充質(zhì)干細(xì)胞移植對(duì)于失血性休克大鼠肺損傷的作用及機(jī)制。方法：選擇40只SD大鼠進(jìn)行實(shí)驗(yàn)，隨機(jī)分為對(duì)照組、休克組、休克+生理鹽水組、休克+干細(xì)胞組。制備失血性休克大鼠模型，并于休克后不同時(shí)間點(diǎn)取材進(jìn)行相關(guān)指標(biāo)的檢測(cè)。結(jié)果：與對(duì)照組相比，休克組的血?dú)夥治?、肺組織學(xué)等指標(biāo)明顯惡化，表現(xiàn)為組織細(xì)胞壞死、肺泡水腫等病理改變；休克+生理鹽水組與休克組差異不明顯；休克+干細(xì)胞組的肺功能、病理學(xué)指標(biāo)均明顯改善。結(jié)論：骨髓間充質(zhì)干細(xì)胞移植可以提高失血性休克大鼠肺功能及減輕肺損傷程度，其作用機(jī)制與降低炎癥反應(yīng)有關(guān)。

關(guān)鍵詞：失血性休克；骨髓間充質(zhì)干細(xì)胞；肺損傷；炎癥反應(yīng)

Abstract:Objective:Toexploretheeffectandmechanismofbonemarrowmesenchymalstemcelltransplantationonlunginjuryinratswithhemorrhagicshock.Methods:40SDratswereselectedfortheexperimentandrandomlydividedintocontrolgroup,shockgroup,shock+salinegroup,andshock+stemcellgroup.Themodelofhemorrhagicshockratswasprepared,andrelevantindicatorsweredetectedatdifferenttimepointsaftershock.Results:Comparedwiththecontrolgroup,thebloodgasanalysis,lunghistologyandotherindicatorsoftheshockgroupweresignificantlyworsened,manifestedaspathologicalchangessuchastissuecellnecrosisandpulmonaryedema;therewasnosignificantdifferencebetweentheshock+salinegroupandtheshockgroup;Lungfunctionandhistologicalindicatorsintheshock+stemcellgroupweresignificantlyimproved.Conclusion:Bonemarrowmesenchymalstemcelltransplantationcanimprovelungfunctionandreducelunginjuryinratswithhemorrhagicshock,anditsmechanismofactionisrelatedtoreducingtheinflammatoryresponse.

Keywords:Hemorrhagicshock;bonemarrowmesenchymalstemcells;lunginjury;inflammatoryresponse。Inrecentyears,hemorrhagicshockhasbecomeamajorcauseofdeathinemergencymedicine.Itischaracterizedbyaseverereductioninbloodvolumeduetointernalorexternalbleeding,whichleadstotissuehypoxiaandorgandysfunction.Oneofthemostaffectedorgansisthelung,whichoftendevelopsacutelunginjuryandacuterespiratorydistresssyndrome(ARDS),resultinginahighmortalityrate.Therefore,findingeffectivetreatmentsforlunginjuryinducedbyhemorrhagicshockiscrucial.

Recentstudieshaveshownthatbonemarrowmesenchymalstemcells(BMSCs)havetherapeuticpotentialforavarietyofdiseasesincludinglunginjury.BMSCspossessanti-inflammatoryandimmunomodulatorypropertiesandcandifferentiateintovariouscelltypesincludinglungepithelialcells.Inthisstudy,weinvestigatedwhetherBMSCscouldimprovelungfunctionandreducelunginjuryinratswithhemorrhagicshock.

OurresultsshowedthatBMSCtransplantationsignificantlyimprovedlungfunctionandreducedlunginjurycomparedtotheshockgroup.Theratsintheshock+salinegroup,whichreceivedsalineinsteadofBMSCs,showednosignificantimprovementinlungfunctionorhistologicalindicators.ThissuggeststhatBMSCsplayacrucialroleinthetherapeuticeffectobservedintheshock+stemcellgroup.

FurtheranalysisshowedthatBMSCtransplantationreducedtheinflammatoryresponseinthelungtissueofratswithhemorrhagicshock.InflammatorycytokinesincludingTNF-αandIL-6weresignificantlydecreasedintheshock+stemcellgroupcomparedtotheshockgroup.ThissuggeststhatthemechanismofactionofBMSCsinreducinglunginjuryisrelatedtotheirabilitytomodulatetheinflammatoryresponse.

Inconclusion,ourstudydemonstratedthatBMSCtransplantationcanimprovelungfunctionandreducelunginjuryinratswithhemorrhagicshock.Thetherapeuticeffectisrelatedtoreducingtheinflammatoryresponseinthelungtissue.Thesefindingsprovideapotentialtherapeuticoptionfortreatinglunginjuryinducedbyhemorrhagicshockinthefuture。FutureDirections

AlthoughourstudyhasdemonstratedthebeneficialeffectsofBMSCtransplantationonlunginjuryinducedbyhemorrhagicshock,therearestillseveralunresolvedissuesthatneedtobeaddressedinfutureresearch.

First,theoptimaltiminganddosageofBMSCtransplantationremainunclear.Inourstudy,wetransplantedBMSCsat1houraftertheonsetofhemorrhagicshock.However,itisunknownwhetherearliertransplantationwouldproducebetteroutcomes.Moreover,theidealdosageofBMSCsneedstobestandardized.

Second,themechanismsunderlyingtheanti-inflammatoryeffectsofBMSCsrequirefurtherexploration.OurstudysuggestedthatBMSCscansuppressthepro-inflammatorycytokineexpressionandactivationofinflammatorycellsinlungtissue,butthespecificmolecularpathwaysinvolvedremainunclear.UnderstandingtheunderlyingmechanismswillnotonlyhelptooptimizethetherapeuticefficacyofBMSCsbutalsodevelopnewpharmacologicaltargetsforcontrollinginflammation.

Third,thepotentialsideeffectsofBMSCtransplantationneedtobeevaluated.AlthoughBMSCtransplantationhasbeenextensivelystudiedforvariousclinicalapplications,thelong-termeffectsonthehost'simmunesystemandtumorigenicityneedtobefurtherelucidated.Moreover,theriskoftransmissionofinfectiousdiseaseshouldalsobecarefullyassessed.

Finally,clinicaltrialsareneededtoconfirmtheeffectivenessandsafetyofBMSCtransplantationintreatinglunginjuryinducedbyhemorrhagicshock.Althoughourresultsarepromising,translationintoclinicalpracticerequiresrigorousevaluationinwell-designedrandomizedcontrolledtrials.

Conclusion

Insummary,ourstudydemonstratedthatBMSCtransplantationcanimprovelungfunctionandreducelunginjuryinducedbyhemorrhagicshockinrats.ThetherapeuticeffectsofBMSCsarerelatedtotheirabilitytomodulatetheinflammatoryresponseinlungtissue.Thesefindingsprovideapotentialtherapeuticoptionfortreatinglunginjuryinducedbyhemorrhagicshockinthefuture.However,morein-depthresearchisneededtooptimizethetherapeuticefficacyandensurethesafetyofBMSCtransplantationinclinicalpractice。Inadditiontohemorrhagicshock-inducedlunginjury,BMSCtransplantationhasbeeninvestigatedforitspotentialtherapeuticeffectsinvariouslungdiseases,includingacuterespiratorydistresssyndrome(ARDS),chronicobstructivepulmonarydisease(COPD),pulmonaryfibrosis,andpulmonaryarterialhypertension(PAH).

SeveralstudieshavedemonstratedthepotentialofBMSCtransplantationintreatingARDS.Forinstance,Liuetal.(2017)reportedthatintravenousinjectionofBMSCscanimprovethesurvivalrateandreducelunginflammationinaratmodeloflipopolysaccharide-inducedARDS.Similarly,Meietal.(2018)showedthatintratrachealtransplantationofBMSC-derivedexosomescanalleviatelunginjuryandimprovelungfunctioninamousemodelofARDSinducedbyacidaspiration.

InCOPD,severalpreclinicalstudieshavereportedthebeneficialeffectsofBMSCtransplantation.Forexample,Chenetal.(2018)demonstratedthatintratrachealinjectionofBMSCscanreduceairwayinflammationandimprovelungfunctioninamousemodelofcigarettesmoke-inducedCOPD.Moreover,Zhangetal.(2019)showedthatintravenoustransplantationofBMSCscanreduceairwayinflammationandemphysemainaratmodelofCOPDinducedbycigarettesmokeexposureandlipopolysaccharide.

Inpulmonaryfibrosis,BMSCtransplantationhasbeenshowntoincreaselungregenerationandreducefibrosis.Forinstance,Leeetal.(2019)reportedthatintratrachealtransplantationofBMSCscanreducefibrosisandimprovelungfunctioninamousemodelofbleomycin-inducedpulmonaryfibrosis.Similarly,Yinetal.(2019)demonstratedthatintravenousinjectionofBMSC-derivedexosomescanattenuatepulmonaryfibrosisandimprovelungfunctioninamousemodelofidiopathicpulmonaryfibrosis.

InPAH,BMSCtransplantationhasbeeninvestigatedasapotentialtherapytoimprovepulmonaryvascularremodelingandreducepulmonaryarterypressure.Forexample,Liangetal.(2017)showedthatintravenoustransplantationofBMSCscanattenuatepulmonaryarteryremodelingandreducepulmonaryhypertensioninaratmodelofPAHinducedbymonocrotaline.Similarly,Lengetal.(2019)demonstratedthatintratrachealtransplantationofBMSCscanreducepulmonaryarterypressureandimprovecardiacfunctioninaratmodelofPAHinducedbychronichypoxiaexposure.

Despitethepromisingresultsofpreclinicalstudies,therearestillchallengesandlimitationsthatneedtobeaddressedbeforeBMSCtransplantationcanbetranslatedintoclinicalpractice.Forinstance,theoptimaldose,route,andtimingofBMSCtransplantationneedtobedeterminedbasedonthespecificdiseaseconditionandthesafetyprofileofBMSCs.Moreover,themechanismsunderlyingthetherapeuticeffectsofBMSCsneedtobeelucidated,aswellasthepotentiallong-termsideeffects,suchastumorigenesisandimmunerejection.Finally,large-scaleclinicaltrialsareneededtoevaluatethesafetyandefficacyofBMSCtransplantationinpatientswithlungdiseases.Overall,BMSCtransplantationholdsgreatpromiseasanoveltherapeuticoptionforlungdiseases,andfurtherresearchiswarrantedtooptimizeitsclinicalapplication。InadditiontothepotentialuseofBMSCsforthetreatmentoflungdiseases,therearealsootherpotentialtherapeuticapplicationsforthesecells.Forexample,BMSCshavebeenshowntohaveatherapeuticeffectinvariousneurologicaldisorders,includingParkinson'sdisease,spinalcordinjury,andstroke.Theyhavealsoshownpromiseforthetreatmentofcardiovasculardiseases,liverdiseases,anddiabetes.ThesediversetherapeuticapplicationsareduetotheuniquepropertiesofBMSCs,includingtheirabilitytodifferentiateintovariouscelltypes,theircapacityforself-renewal,andtheirabilitytomodulateimmuneresponsesandtissuerepairprocesses.

DespitetheexcitingpotentialofBMSCsfortherapeuticapplications,therearealsosomechallengestoovercome.Forexample,thereisaneedtodevelopmoreefficientmethodsforisolatingandexpandingBMSCs,ascurrentmethodsaretime-consumingandexpensive.ThereisalsoaneedtostandardizethecharacterizationofBMSCs,asdifferentlaboratoriesoftenusedifferentmethodstodefinethesecells.Furthermore,thereisaneedtooptimizethedeliveryofBMSCstotargettissues,astheoptimaldoseandrouteofadministrationfordifferentdiseasesmayvary.

Inconclusion,BMSCsrepresentapromisingtherapeuticoptionforthetreatmentoflungdiseasesandothermedicalconditions.Whiletherearestillmanychallengestoovercome,thepotentialbenefitsofBMSCtransplantationaresignificant,andongoingresearchinthisfieldislikelytoleadtofurtheradvancesinregenerativemedicine。OneareaofresearchthatholdsgreatpromiseforthefutureofBMSCtransplantationistheuseoftissueengineeringtechniquestocreatefunctionallungtissueinthelaboratory.Thisapproachinvolvesgrowinglungcellsonascaffold,whichprovidesmechanicalsupportandpromotestheformationofnewtissue.Oncethetissuehasmatured,itcanbeimplantedintothepatient,bypassingtheneedfordonororgansandreducingtheriskofrejection.

OtherpromisingavenuesofresearchincludetheuseofgeneeditingtechniquestomodifyBMSCsbeforetransplantation,allowingthemtotargetspecificcellsortissuesmoreeffectively.Inaddition,researchersareexploringtheuseofadvancedimagingtechniquestotrackthemigrationandengraftmentoftransplantedcellsinrealtime,allowingformoreprecisedosingandmonitoringoftherapeuticoutcomes.

Despitetheseadvances,therearestillsignificantchallengesthatneedtobeaddressedinordertomakeBMSCtransplantationaviableoptionforwidespreadclinicaluse.Forexample,efficientmethodsofharvestingandculturingBMSCsneedtobedeveloped,andthelong-termsafetyofthesecellsmustbethoroughlytested.Inaddition,thereisaneedforstandardizedprotocolsforevaluatingtheefficacyandsafetyofBMSCtransplantationacrossdifferentdiseaseindications.

Nevertheless,thepotentialbenefitsofBMSCtransplantationforthetreatmentoflungdiseasesandothermedicalconditionsareclear,andongoingresearchinthisfieldislikelytopavethewayfornewandinnovativetherapeuticapproachesthatcouldtransformthefieldofregenerativemedicine.Withcontinuedinvestmentandcollaborationbetweenresearchers,clinicians,andindustrypartners,BMSCtransplantationhasthepotentialtorevolutionizepatientcareandimproveoutcomesforcountlessindividualsaroundtheworld。Inadditiontoitspotentialintreatinglungdiseases,BMSCtransplantationhasalsoshownpromiseinothermedicalconditions.Forexample,studieshaveshownthatBMSCtransplantationmayhavetherapeuticeffectsinneurologicaldisorderssuchasParkinson'sdiseaseandmultiplesclerosis.Inonestudy,researcherstransplantedBMSCsintothebrainsofmicewithParkinson'sdiseaseandobservedasignificantimprovementinmotorfunctioncomparedtocontrolmice.Similarly,inaclinicaltrialinvolvingpatientswithmultiplesclerosis,BMSCtransplantationwasfoundtoimproveclinicaloutcomesandreducediseaseactivity.

BMSCtransplantationhasalsobeenexploredasapotentialtreatmentforcardiovasculardiseasessuchasmyocardialinfarctionandheartfailure.Inastudyinvolvingratswithmyocardialinfarction,researcherstransplantedBMSCsintotheheartandfoundthatitpromotedangiogenesis,reducedinflammation,andimprovedheartfunction.Similarresultshavebeenobservedinclinicaltrialsinvolvingpatientswithheartfailure,withBMSCtransplantationsignificantlyimprovingheartfunctionandreducingmortalityrates.

OtherpotentialapplicationsofBMSCtransplantationincludethetreatmentofboneandjointdisorders,skininjuries,andautoimmunediseases.Inaclinicaltrialinvolvingpatientswithrheumatoidarthritis,forexample,BMSCtransplantationwasfoundtoreduceinflammationandimp