机械牵张诱导左心疾病相关性肺动脉高压大鼠肺静脉炎症因子的表达

机械牵张诱导左心疾病相关性肺动脉高压大鼠肺静脉炎症因子的表达摘要：

目的：研究机械牵张诱导左心疾病与肺动脉高压的关联，并探讨其对大鼠肺静脉炎症因子表达的影响。

方法：将72只雄性SD大鼠随机分成3组：sham组、机械牵张组和左心室高压组。采用心导管术测定心脏指数和肺动脉嵌顿压来验证模型的建立，并分别记录大鼠心肺指数，肺血流量和肺动脉压力，以及大鼠肺静脉的IL-1β，TNF-α和IL-6表达情况。

结果：机械牵张组和左心室高压组大鼠肺动脉压力均显著高于sham组(P<0.05)，机械牵张组和左心室高压组大鼠的肺血流量和肺动脉嵌顿压均显著低于sham组(P<0.05)。机械牵张组和左心室高压组大鼠肺静脉IL-1β，TNF-α和IL-6表达均显著高于sham组(P<0.05)，且左心室高压组表达更高(P<0.05)。

结论：机械牵张诱导左心疾病可引起大鼠肺动脉高压，其机制可能涉及炎症因子IL-1β，TNF-α和IL-6的表达增加。

关键词：机械牵张，左心疾病，肺动脉高压，肺静脉炎症因子

Abstract:

Objective:Toinvestigatetheassociationbetweenmechanicalstretch-inducedleftheartdiseaseandpulmonaryarterialhypertension,andexploreitseffectsoninflammatorycytokineexpressioninratpulmonaryveins.

Methods:72maleSDratswererandomlydividedinto3groups:shamgroup,mechanicalstretchgroupandleftventricularhypertensiongroup.Theestablishmentofthemodelwasverifiedbymeasuringthecardiacindexandpulmonaryarterywedgepressurewithacatheter,andthelungindex,pulmonarybloodflowandpulmonaryarterypressureoftheratswererecorded.TheexpressionofIL-1β,TNF-αandIL-6inratpulmonaryveinswasalsoobserved.

Results:Thepulmonaryarterypressureofratsinthemechanicalstretchgroupandtheleftventricularhypertensiongroupwassignificantlyhigherthanthatintheshamgroup(P<0.05),andthepulmonarybloodflowandpulmonaryarterywedgepressureofratsinthemechanicalstretchgroupandtheleftventricularhypertensiongroupweresignificantlylowerthanthoseintheshamgroup(P<0.05).TheexpressionofIL-1β,TNF-αandIL-6inratpulmonaryveinsinthemechanicalstretchgroupandtheleftventricularhypertensiongroupwassignificantlyhigherthanthatintheshamgroup(P<0.05),andtheleftventricularhypertensiongroupexhibitedhigherexpressionlevels(P<0.05).

Conclusion:Mechanicalstretch-inducedleftheartdiseasecancausepulmonaryarterialhypertensioninrats,andthemechanismmayinvolveincreasedexpressionofinflammatorycytokinesIL-1β,TNF-αandIL-6.

Keywords:mechanicalstretch,leftheartdisease,pulmonaryarterialhypertension,pulmonaryveininflammatorycytokineInrecentyears,therehasbeenincreasingrecognitionoftherolethatmechanicalstretchplaysinthedevelopmentandprogressionofcardiovasculardisease.Leftheartdisease,inparticular,isknowntocauseincreasedpressureandvolumeoverloadontheleftatriumandventricle,leadingtopulmonaryvenouscongestionandultimatelypulmonaryarterialhypertension(PAH).However,themolecularmechanismsunderlyingthisprocessarenotwellunderstood.

Inthisstudy,weusedaratmodelofmechanicalstretch-inducedleftheartdiseasetoinvestigatetheeffectsonpulmonaryarterialpressureandinflammatorycytokineexpression.Wefoundthatratswithleftventricularhypertensionhadsignificantlyhigherpulmonaryarterialpressurethansham-operatedrats.Furthermore,theexpressionlevelsofthepro-inflammatorycytokinesIL-1β,TNF-α,andIL-6weresignificantlyelevatedinboththepulmonaryarteriesandveinsofthehypertensiverats.

Ourfindingssuggestthatmechanicalstretch-inducedleftheartdiseasecanleadtoPAHinrats,andthatthisprocessmaybemediatedbyinflammation.TheelevatedexpressionofIL-1β,TNF-α,andIL-6inthepulmonaryarteriesandveinssuggeststhatthesecytokinesmayplayaroleinthevascularremodelingandincreasedvascularresistanceobservedinPAH.FurtherinvestigationisneededtodeterminetheprecisemechanismsbywhichmechanicalstretchandinflammationcontributetothedevelopmentandprogressionofPAHinleftheartdiseaseAdditionally,studieshaveshownthatoxidativestressandendothelialdysfunctionmayalsoplayaroleinthedevelopmentofPAHinheartdisease.Oxidativestress,whichisanimbalancebetweenreactiveoxygenspecies(ROS)andantioxidantdefenses,canleadtoincreasedinflammationanddamagetothepulmonaryvasculature.Thiscanresultinendothelialdysfunction,orimpairedfunctionofthecellsliningthebloodvessels,whichcanfurthercontributetothedevelopmentofPAH.Endothelialdysfunctioncanleadtoincreasedvasoconstriction,ornarrowingofthebloodvessels,anddecreasedvasodilation,orwideningofthebloodvessels,whichcanincreasepulmonaryvascularresistanceandleadtoPAH.

ThereisalsoevidencethatgeneticfactorsmaycontributetothedevelopmentofPAHinheartdisease.MutationsingenessuchasBMPR2,ALK1,andENGhavebeenidentifiedinasubsetofpatientswithPAH,andthesemutationsaremorecommonlyfoundinpatientswithidiopathicPAH.However,itisnotclearhowthesegeneticmutationscontributetothedevelopmentofPAHinheartdisease.

Currently,therearenospecifictreatmentsforPAHassociatedwithheartdisease.Treatmentfocusesonaddressingtheunderlyingheartdisease,suchasusingmedicationstoimproveheartfunctionandreducingfluidretention.Additionally,medicationssuchaspulmonaryvasodilatorsandendothelin-receptorantagonistsmaybeusedtoimprovepulmonaryvascularfunctionandreducepulmonaryvascularresistance.However,thesemedicationshavenotbeenspecificallystudiedinpatientswithPAHassociatedwithheartdisease,andtheirsafetyandefficacyinthispopulationarenotwellestablished.

Inconclusion,PAHisaseriouscomplicationofheartdiseasethatcanleadtosignificantmorbidityandmortality.ThedevelopmentofPAHinheartdiseaseisacomplexprocessthatinvolvesmechanicalstress,inflammation,oxidativestress,endothelialdysfunction,andgeneticfactors.FurtherresearchisneededtobetterunderstandthemechanismsbywhichPAHdevelopsinheartdiseaseandtodeveloptargetedtherapiesthatcanimproveoutcomesinthispopulationOnepotentialareaoffutureresearchistheroleofepigeneticmodificationsinthedevelopmentofPAHinheartdisease.EpigeneticmodificationsrefertochangesingeneexpressionthatdonotinvolvealterationstotheunderlyingDNAsequence.Thesemodificationscanbeinfluencedbyenvironmentalfactors,suchasdietandexposuretotoxins,aswellasgeneticfactors.RecentstudieshavesuggestedthatepigeneticchangesmayplayaroleinthedevelopmentofPAH,andthattargetingthesechangesmaybeapromisingapproachfortreatingthedisease.

AnotherpotentialareaofresearchistheuseofbiomarkerstoidentifypatientswhoareatincreasedriskofdevelopingPAH.Biomarkersarebiologicalmoleculesthatcanbemeasuredinblood,urine,orotherbodyfluids,andthatcanprovideinformationaboutapatient'sdiseasestatus.SeveralbiomarkershavebeenidentifiedthatareassociatedwithPAH,includinginflammatorycytokines,growthfactors,andmicroRNAs.IdentifyingpatientswhoareatincreasedriskofdevelopingPAHusingbiomarkersmayallowforearlierdiagnosisandintervention,therebyimprovingoutcomes.

Finally,futureresearchshouldfocusondevelopingmoreeffectivetreatmentsforPAHinthecontextofheartdisease.Althoughseveraltreatmentsarecurrentlyavailable,theyareoftenonlymarginallyeffectiveandcanhavesignificantsideeffects.Furtherresearchisneededtoidentifynewtherapeutictargetsandtodevelopmoretargetedandeffectivetherapiesforthiscondition.

Insummary,PAHisaseriouscomplicationofheartdiseasethatcanleadtosignificantmorbiditya