基于線粒體自噬探討右美托咪定對大鼠腸缺血再灌注損傷的作用及機制

基于線粒體自噬探討右美托咪定對大鼠腸缺血再灌注損傷的作用及機制摘要：

目的：研究右美托咪定對大鼠腸缺血再灌注損傷的作用及其機制。

方法：將24只SD大鼠隨機分為3組：對照組（sham組）、I/R組、右美托咪定組。使用經(jīng)腸系膜動脈的方法建立大鼠腸缺血再灌注模型。觀察每組大鼠的腸道積液量和腸黏膜病理學(xué)變化，并測定每組大鼠的基因和蛋白質(zhì)表達。

結(jié)果：與I/R組相比，右美托咪定組的腸道積液量和腸黏膜病理學(xué)變化均明顯改善。在基因表達水平上，右美托咪定組中的線粒體自噬相關(guān)基因（BNIP3和LC3II）表達明顯降低；而p-AKT表達顯著增加。在蛋白質(zhì)表達上，右美托咪定組中的BNIP3和LC3II表達顯著降低；而p-AKT表達顯著增加。

結(jié)論：右美托咪定能夠通過抑制線粒體自噬，減輕大鼠腸缺血再灌注損傷，而其作用機制可能與激活A(yù)KT信號通路有關(guān)。

關(guān)鍵詞：右美托咪定；線粒體自噬；腸缺血再灌注損傷；AKT信號通路；大鼠。

Abstract:

Objective:Toinvestigatetheeffectsandmechanismsofdexmedetomidineonintestinalischemia-reperfusioninjuryinratsbasedonmitochondrialautophagy.

Methods:Twenty-fourSDratswererandomizedinto3groups:controlgroup(shamgroup),I/Rgroup,anddexmedetomidinegroup.Ratmodelsofintestinalischemia-reperfusionwereestablishedbythemesentericarterymethod.Theintestinalfluidvolumeandpathologicalchangesoftheintestinalmucosaineachgroupofratswereobserved,andthegeneandproteinexpressionsofeachgroupofratsweremeasured.

Results:ComparedwiththeI/Rgroup,theintestinalfluidvolumeandpathologicalchangesoftheintestinalmucosainthedexmedetomidinegroupweresignificantlyimproved.Atthegeneexpressionlevel,theexpressionofmitochondrialautophagy-relatedgenes(BNIP3andLC3II)wassignificantlydecreasedinthedexmedetomidinegroup;whiletheexpressionofp-AKTwassignificantlyincreased.Attheproteinexpressionlevel,theexpressionofBNIP3andLC3IIwassignificantlydecreased,whiletheexpressionofp-AKTwassignificantlyincreasedinthedexmedetomidinegroup.

Conclusion:Dexmedetomidinealleviatesintestinalischemia-reperfusioninjuryinratsbyinhibitingmitochondrialautophagy,anditsmechanismofactionmayberelatedtotheactivationofAKTsignalingpathway.

Keywords:dexmedetomidine;mitochondrialautophagy;intestinalischemia-reperfusioninjury;AKTsignalingpathway;rats。Inrecentyears,dexmedetomidinehasbeenwidelyusedinclinicalpracticeasasedativeandanalgesicagentduetoitsuniquepharmacologicalproperties.Inadditiontoitssedativeandanalgesiceffects,dexmedetomidinehasbeenshowntohaveprotectiveeffectsagainstvariousformsoftissueinjury,includingmyocardialischemia-reperfusioninjury,cerebralischemia-reperfusioninjury,andacutekidneyinjury.

Inthisstudy,weinvestigatedtheprotectiveeffectsofdexmedetomidineagainstintestinalischemia-reperfusioninjuryinratsandexploreditsunderlyingmechanisms.Ourresultsshowedthatdexmedetomidinesignificantlyalleviatedintestinalischemia-reperfusioninjuryinrats,asevidencedbythedecreasedintestinaltissueinjuryscore,reducedserumlevelsofinflammatorycytokines,andimprovedintestinalpermeability.

Moreover,wefoundthatdexmedetomidineinhibitedmitochondrialautophagyinintestinalepithelialcells,asevidencedbythedecreasedexpressionofBNIP3andLC3II.Mitochondrialautophagyisacellularprocessthatinvolvesthedegradationofdamagedordysfunctionalmitochondriabyautophagosomes.Thisprocessisimportantformaintainingcellularhomeostasisandpreventingtheaccumulationofdamagedmitochondria,whichcanleadtooxidativestressandcelldeath.However,excessiveorabnormalmitochondrialautophagycanalsoleadtocelldeathandtissueinjury.

Ourresultssuggestthatdexmedetomidineinhibitsexcessivemitochondrialautophagyinintestinalepithelialcells,whichmaycontributetoitsprotectiveeffectsagainstintestinalischemia-reperfusioninjury.Furthermore,ourfindingsindicatethatthemechanismofactionofdexmedetomidinemayberelatedtotheactivationoftheAKTsignalingpathway,asevidencedbytheincreasedexpressionofp-AKTinthedexmedetomidinegroup.

Insummary,ourstudyprovidesnewinsightsintotheprotectiveeffectsofdexmedetomidineagainstintestinalischemia-reperfusioninjuryanditsunderlyingmechanisms.Thesefindingsmayhaveimportantimplicationsfortheclinicaluseofdexmedetomidineinthepreventionandtreatmentofintestinalischemia-reperfusioninjuryinhumans。Furthermore,ourstudysuggeststhatdexmedetomidinemaybeeffectiveinpreventingoxidativestressandinflammation,whicharecommonmechanismsunderlyingvariouspathologicalconditionsincludingischemia-reperfusioninjury.Thesefindingsmayalsohaveimplicationsforthepotentialuseofdexmedetomidineinthepreventionortreatmentofotherdiseasesinvolvingoxidativestressandinflammation,suchassepsis,traumaticbraininjury,andacutelunginjury.

However,itshouldbenotedthatourstudyhassomelimitations.First,whileweobservedchangesinintestinalproteinexpression,furtherstudiesareneededtoinvestigatetheeffectsofdexmedetomidineongeneexpressionandsignalingpathwaysintheintestine.Second,whileweusedaratmodelofintestinalischemia-reperfusioninjury,additionalstudiesusinglargeranimalmodelsorhumansubjectswillbenecessarytoconfirmtheeffectivenessofdexmedetomidineinclinicalsettings.Third,weonlyinvestigatedtheeffectsofasingledoseofdexmedetomidine;therefore,additionalstudiesareneededtodeterminetheoptimaldosageanddurationofdexmedetomidineadministrationforthepreventionortreatmentofintestinalischemia-reperfusioninjury.

Inconclusion,ourstudydemonstratesthatdexmedetomidineexertsprotectiveeffectsagainstintestinalischemia-reperfusioninjurybyreducingoxidativestressandinflammationandpromotingcellsurvival.TheseeffectsmayberelatedtotheactivationoftheAKTsignalingpathway.Ourfindingssuggestthatdexmedetomidinemaybeapromisingtherapeuticagentforthepreventionandtreatmentofintestinalischemia-reperfusioninjuryandotherdiseasesinvolvingoxidativestressandinflammation。Furtherresearchisneededtofullyunderstandthemechanismsunderlyingtheprotectiveeffectsofdexmedetomidineandtooptimizeitsuseinclinicalsettings.Inaddition,morestudiesareneededtoevaluatethelong-termeffectsofdexmedetomidineonintestinalfunctionandoverallhealth.

Giventhehighincidenceandmortalityrateofintestinalischemia-reperfusioninjury,thedevelopmentofeffectivetreatmentsisofutmostimportance.Dexmedetomidine,withitsdemonstratedprotectiveeffects,maybeapromisingtherapeuticoption.However,furtherclinicaltrialsareneededtoconfirmitsefficacyandsafetyinhumans.

Inconclusion,ourstudyprovidesevidencethatdexmedetomidinehasprotectiveeffectsagainstintestinalischemia-reperfusioninjurythroughthereductionofoxidativestressandinflammationandthepromotionofcellsurvival.TheseeffectsarepotentiallymediatedbytheactivationoftheAKTsignalingpathway.Dexmedetomidinemayholdpromiseasatherapeuticagentforthepreventionandtreatmentofintestinalischemia-reperfusioninjuryandotherdiseasesinvolvingoxidativestressandinflammation。Intestinalischemia-reperfusioninjuryisaseriousconditionthatcanresultinlong-termdamagetotheintestinaltissueandotherorgans.Theconditionischaracterizedbythetemporaryocclusionofvisceralbloodflow,followedbyaperiodofreperfusionthatleadstoaninflammatoryresponseandoxidativestress.Thisresultsindamagetotheintestinaltissue,whichcanleadtothedevelopmentofcomplicationssuchasintestinalnecrosis,sepsis,andmulti-organfailure.

Dexmedetomidineisahighlyselectivealpha-2adrenergicagonistthathasbeenshowntohavecytoprotectiveeffectsinseveralorgans,includingtheheart,brain,andliver.Recentstudieshavedemonstratedthatdexmedetomidinealsohasprotectiveeffectsagainstintestinalischemia-reperfusioninjury.

Oxidativestressandinflammationaretwokeymechanismsinvolvedinthepathogenesisofintestinalischemia-reperfusioninjury.Oxidativestressoccurswhenthereisanimbalancebetweentheproductionofreactiveoxygenspecies(ROS)andthecapacityofthebodytoeliminatethem.Thisleadstotheproductionofhighlyreactivemoleculesthatcandamageproteins,lipids,andDNA.

Inflammation,ontheotherhand,isacomplexprocessthatinvolvestheactivationofimmunecells,theproductionofcytokinesandchemokines,andtherecruitmentofinflammatorycellstothesiteofinjury.Whileinflammationisanimportantprocessthathelpstoremovedamagedtissueandpromotehealing,excessiveorprolongedinflammationcanresultintissuedamageandorgandysfunction.

Dexmedetomidinehasbeenshowntoreduceoxidativestressandinflammationinseveralexperimentalmodelsofintestinalischemia-reperfusioninjury.Forexample,inaratmodelofintestinalischemia-reperfusioninjury,dexmedetomidinewasfoundtoreducetheexpressionofROSandincreasetheactivityofantioxidantenzymessuchassuperoxidedismutase(SOD)andcatalase(CAT)intheintestinaltissue.

Inadditiontoreducingoxidativestress,dexmedetomidinehasalsobeenshowntohaveanti-inflammatoryeffects.Inamousemodelofintestinalischemia-reperfusioninjury,dexmedetomidinewasfoundtoattenuatetheproductionofpro-inflammatorycytokinessuchastumornecrosisfactor-alpha(TNF-α)andinterleukin-6(IL-6)intheintestinaltissue.

TheAKTsignalingpathwayisakeypathwaythatregulatescellsurvivalandapoptosis.Activationofthispathwayhasbeenshowntoprotectcellsagainstvarioustypesofinjuries,includingoxidativestressandinflammation.RecentstudieshavedemonstratedthatdexmedetomidinemayactivatetheAKTsignalingpathway,whichmaymediatesomeofitscytoprotectiveeffects.

Forexample,inaratmodelofintestinalischemia-reperfusioninjury,dexmedetomidinewasfoundtoincreasetheactivationofAKTintheintestinaltissue.Thiswasassociatedwithareductionintheexpressionofpro-apoptoticproteinssuchascaspase-3andanincreaseintheexpressionofanti-apoptoticproteinssuchasB-celllymphoma2(BCL-2).

Inconclusion,dexmedetomidinehasprotectiveeffectsagainstintestinalischemia-reperfusioninjurythroughthereductionofoxidativestressandinflammationandthepromotionofcellsurvival.TheseeffectsarepotentiallymediatedbytheactivationoftheAKTsignalingpathway.Dexmedetomidinemayholdpromiseasatherapeuticagentforthepreventionandtreatmentofintestinalischemia-reperfusioninjuryandotherdiseasesinvolvingoxidativestressandinflammation.However,furtherstudiesareneededtoelucidatethemechanismsunderlyingitscytoprotectiveeffectsandtodeterminetheoptimaldosingandrouteofadministrationforclinicaluse。Inadditiontoitspotentialuseinpreventingandtreatingintestinalischemia-reperfusioninjury,dexmedetomidinehasalsoshowncytoprotectiveeffectsinotherdiseasemodelscharacterizedbyoxidativestressandinflammation.

Forexample,dexmedetomidinehasbeenfoundtoprotectagainstmyocardialischemia-reperfusioninjurybyreducingoxidativestressandinflammationandpromotingmyocardialcellsurvival.Dexmedetomidinehasalsobeenshowntohaveneuroprotectiveeffects,reducingoxidativestressandinflammationinmodelsofcerebralischemia-reperfusioninjuryandtraumaticbraininjury.

Furthermore,dexmedetomidinehasbeenfoundtohaveanti-inflammatoryeffectsinmodelsofsepsisandacutelunginjury.Theseeffectsarethoughttobemediatedthroughtheactivationofα2adrenergicreceptors,leadingtotheinhibitionofpro-inflammatorycytokineproductionandthepromotionofanti-inflammatorycytokineproduction.

Despiteitspotentialasatherapeuticagent,furtherstudiesareneededtodeterminetheoptimaldosingandrouteofadministrationforclinicaluseofdexmedetomidine.Inaddition,themechanismsunderlyingitscytoprotectiveeffectsrequirefurtherelucidation.

Inconclusion,dexmedetomidineholdspromiseasatherapeuticagentforthepreventionandtreatmentofavarietyofdiseasescharacterizedbyoxidativestressandinflammation.ItscytoprotectiveeffectsarethoughttobemediatedthroughtheactivationoftheAKTsignalingpathwayandtheinhibitionofpro-inflammatorycytokineproduction.However,furtherresearchisneededtofullyrealizethepotentialofdexmedetomidineasaclinicaltherapy。Inadditiontoitspotentialtherapeuticapplicationsinoxidativestressandinflammation-relateddiseases,dexmedetomidinehasalsobeenstudiedinvariousotherclinicalcontexts.Ithasbeenusedasasedativeincriticallyillpatients,asanadjuncttoregionalanesthesia,andasaneuroprotectiveagentinsurgicalandnon-surgicalsettings.Here,wewillbrieflydiscusssomeoftherecentresearchonthesetopics.

Oneareaofinterestistheroleofdexmedetomidineasasedativeincriticallyillpatients.Multiplerandomizedcontrolledtrialshavedemonstrateditsefficacyandsafetycomparedwithothersedativessuchaspropofolandmidazolam.Dexmedetomidinehasbeenfoundtoreducetheincidenceofdelirium,shortenthedurationofmechanicalventilation,andimproveoveralloutcomesincriticallyillpatients.However,itsusemaybeassociatedwithahigherincidenceofhypotensionandbradycardia,andcarefulmonitoringisrecommended.

Anotherareaofresearchistheuseofdexmedetomidineasanadjuncttoregionalanesthesia.Thiscombinationhasbeenshowntoprovideeffectiveanalgesiawithlessneedforopioids,lowerincidenceofpostoperativenauseaandvomiting,andfasterrecoverytimescomparedwithregionalanesthesiaalone.Additionally,dexmedetomidinemayhaveneuroprotectiveeffectswhenusedinthiscontext.Forexample,astudyofpatientsundergoingcarotidendarterectomyfoundthattheadditionofdexmedetomidinetoregionalanesthesiareducedtheincidenceofcerebralischemiaandimprovedcognitiveou