基于TLR4-RhoA信號通路研究連續(xù)血液濾過治療燒傷膿毒癥對血管內(nèi)皮細胞通透性的影響

基于TLR4-RhoA信號通路研究連續(xù)血液濾過治療燒傷膿毒癥對血管內(nèi)皮細胞通透性的影響基于TLR4/RhoA信號通路研究連續(xù)血液濾過治療燒傷膿毒癥對血管內(nèi)皮細胞通透性的影響

摘要：燒傷膿毒癥是燒傷后嚴重的并發(fā)癥之一，其病理生理過程與血管內(nèi)皮細胞通透性的增加密切相關(guān)。在現(xiàn)代醫(yī)學中，連續(xù)血液濾過具有很好的治療效果，但其對血管內(nèi)皮細胞通透性的影響尚未充分研究。本研究以TLR4/RhoA信號通路為重點，采用了免疫熒光、Westernblot、組織學等技術(shù)手段，分別觀察和分析連續(xù)血液濾過前后燒傷膿毒癥模型大鼠血管內(nèi)皮細胞的形態(tài)、通透性及TLR4/RhoA信號通路相關(guān)蛋白的表達變化。結(jié)果表明，連續(xù)血液濾過治療可以顯著降低燒傷膿毒癥大鼠血管內(nèi)皮細胞通透性，同時也可以抑制TLR4/RhoA信號通路的活化，從而改善血管內(nèi)層的功能。因此，本研究為連續(xù)血液濾過在治療燒傷膿毒癥中的應用提供了新的理論依據(jù)和實驗依據(jù)。

關(guān)鍵詞：連續(xù)血液濾過；燒傷膿毒癥；血管內(nèi)皮細胞通透性；TLR4/RhoA信號通路。

Abstract:Burnsepsisisoneoftheseriouscomplicationsafterburns,anditspathophysiologicalprocessiscloselyrelatedtotheincreasedpermeabilityofvascularendothelialcells.Inmodernmedicine,continuoushemofiltrationhasagoodtherapeuticeffect,butitseffectonthepermeabilityofvascularendothelialcellshasnotbeenfullystudied.Inthisstudy,focusedontheTLR4/RhoAsignalingpathway,immunofluorescence,Westernblot,histologyandothertechnicalmeanswereusedtoobserveandanalyzethemorphology,permeabilityandexpressionofTLR4/RhoAsignalingpathway-relatedproteinsinthevascularendothelialcellsofburnsepsismodelratsbeforeandaftercontinuoushemofiltration.Theresultsshowedthatcontinuoushemofiltrationtreatmentcouldsignificantlyreducethepermeabilityofvascularendothelialcellsinburnsepsisrats,andalsoinhibittheactivationoftheTLR4/RhoAsignalingpathway,therebyimprovingthefunctionofthevascularintima.Therefore,thisstudyprovidesnewtheoreticalandexperimentalevidencefortheapplicationofcontinuoushemofiltrationinthetreatmentofburnsepsis.

Keywords:continuoushemofiltration;burnsepsis;permeabilityofvascularendothelialcells;TLR4/RhoAsignalingpathwayBurnsepsisisalife-threateningconditionthatresultsfromsevereburninjuriesandsubsequentinfections.Itisacomplexpathologicalprocessinvolvingtheactivationofmultiplepathwaysandthedysfunctionofvariousorgans.Continuoushemofiltration(CHF)isawidelyusedrenalreplacementtherapyincriticalcaremedicine,whichhasshownpromisingresultsinthetreatmentofburnsepsis.

Inthisstudy,weinvestigatedtheeffectsofCHFonthepermeabilityofvascularendothelialcellsandtheTLR4/RhoAsignalingpathwayinburnsepsisrats.OurresultsdemonstratedthatCHFcansignificantlyreducethepermeabilityofvascularendothelialcellsinburnsepsisrats,suggestingthatitmayimprovetheintegrityandfunctionofthevascularintima.Furthermore,CHFtreatmentwasfoundtoinhibittheactivationoftheTLR4/RhoAsignalingpathway,whichisknowntoplayacrucialroleinthedevelopmentofsepsis-inducedvasculardysfunction.

TheTLR4/RhoAsignalingpathwayisacomplexsignalingpathwayinvolvedintheactivationofinflammatoryresponsesandtheregulationofvascularpermeability.Ithasbeenshowntobeupregulatedinsepsisandtocontributetothepathologicalchangesinthevascularendothelium.OurstudyprovidesnewinsightsintothepotentialmechanismsbehindthebeneficialeffectsofCHFinburnsepsis,andhighlightstheimportanceoftargetingtheTLR4/RhoApathwayinthetreatmentofthiscondition.

Inconclusion,ourfindingssuggestthatCHFcanreducethepermeabilityofvascularendothelialcellsandinhibittheactivationoftheTLR4/RhoAsignalingpathwayinburnsepsisrats.TheseresultsprovidenewevidencefortheuseofCHFinthetreatmentofburnsepsis,andmayhavesignificantclinicalimplicationsforimprovingpatientoutcomesincriticalcaresettingsFurtherstudiesareneededtoexploretheunderlyingmechanismsbywhichCHFexertsitseffectsontheTLR4/RhoApathwayinburnsepsis.Additionally,itwouldbevaluabletoinvestigatetheoptimaldosingandtimingofCHFadministrationforthetreatmentofburnsepsis.

Moreover,itshouldalsobenotedthatthisstudywasfocusedonanimalmodels,andtheresultsmaynotnecessarilytranslatedirectlytohumanpatients.Therefore,itwillbeimportanttoconductclinicaltrialstoconfirmtheefficacyandsafetyofCHFinthetreatmentofburnsepsis.

TherearealsootherpotentialtherapeutictargetsintheTLR4/RhoApathwaythatcouldbeexploredforthetreatmentofburnsepsis.Forexample,blockingTLR4itselfordownstreameffectorsofRhoAcouldalsobeeffectivestrategies.

Overall,thefindingsofthisstudysuggestthatCHFmaybeapromisingtherapyforburnsepsis,andthattargetingtheTLR4/RhoApathwaycouldbeafruitfulapproachforthedevelopmentofnewtreatmentsforthiscondition.FurtherresearchisneededtofullyunderstandthemechanismsunderlyingCHF'seffects,andtotranslatethesefindingsintoclinicalpracticeInadditiontotargetingtheTLR4/RhoApathway,theremaybeotherpotentialavenuesfortreatingburnsepsis.Forexample,immunomodulatorytherapiessuchascytokineblockersorimmunoglobulintherapyhaveshownpromiseinanimalmodelsofsepsis,andcouldbeexploredfurtherforuseinburnsepsis.

Anotherpotentialapproachcouldbetheuseofprobioticsorfecalmicrobiotatransplantation(FMT)torestoreahealthymicrobiomeinburnpatients.Burninjuriescandisruptthegutmicrobiomeandincreasetheriskofsepsis,sorestoringahealthymicrobialcommunitycouldreducethisrisk.Inastudyusingamousemodelofburninjury,FMTfromhealthymicewasabletorestorethegutmicrobiomeandimprovesurvivalratesfollowingsepsis.

Finally,itisimportanttoemphasizetheimportanceofearlydetectionandtreatmentofsepsisinburnpatients.Rapiddiagnosisandappropriateantibiotictherapycanbelife-savingincasesofsepsis,andeffortsshouldbemadetoensuretimelyrecognitionandmanagementofthisconditioninburnpatients.

Insummary,burnsepsisisaseriouscomplicationthatcanleadtosignificantmorbidityandmortalityinburnpatients.CHFrepresentsapromisingtherapyforthiscondition,andtargetingtheTLR4/RhoApathwaymaybeafruitfulapproachfordevelopingnewtreatments.However,furtherresearchisneededtofullyunderstandthemechanismsunderlyingCHF'seffects,andtotranslatethesefindingsintoclinicalpractice.Otherpotentialstrategiesfortreatingburnsepsisincludeimmunomodulatorytherapies,probiotics/FMT,andearlydetectionandtreatmentofsepsis.Ultimately,thesuccessfulmanagementofburnsepsiswillrequireamultifacetedapproachthataddressesboththehostre