细胞外组蛋白在急性肝衰竭小鼠中的变化.docVIP

PAGE PAGE 1 细胞外组蛋白在急性肝衰竭小鼠中的变化 　　【摘要】目的研究急性肝衰竭小鼠细胞外组蛋白的水平变化及干预价值。方法选野生型C57BL/6小鼠，经腹腔注射致死剂量的D-氨基半乳糖和脂多糖诱导急性肝衰竭，动态测定血浆中细胞外组蛋白的水平以及肝功能、细胞凋亡等指标；分别给予特异性抗组蛋白H3和H4中和抗体进行干预，并检测小鼠生存率和肝损伤指标以及肿瘤坏死因子TNF-α水平等。结果D-氨基半乳糖和脂多糖联用导致小鼠急性肝衰竭，表现为血浆ALT水平明显升高，大量肝细胞凋亡和坏死，所有小鼠于9～12h内死亡；染毒后小鼠细胞外组蛋白水平呈时间依赖方式明显增高，和对照组相比差异具有统计学意义（P-α水平有关。结论细胞外组蛋白是肝衰竭发病过程中的重要炎性介质，以细胞外组蛋白为靶点进行干预可能是今后重型肝炎治疗的新策略，值得深入探讨。 　　【关键词】细胞外组蛋白；肝衰竭；细胞凋亡；中和抗体；炎症；肿瘤坏死因子-α 　　ChangesofextracellularhistonesinmicewithacuteliverfailureanditstherapeuticpotentialWENTao，GOUChun-yan，LUJing，LIUYan，PIAOZheng-fu，LIFeng，CHENDe-xi.BeijingInstituteofHepatology，BeijingYouanHospitalAffiliatedwithCapitalMedicalUniversity，Beijing100069，China 　　Correspondingauthor：CHENDe-xi，Email：dexi09@ 　　【Abstract】ObjectiveToinvestigatethechangesofextracellularhistonesduringthecourseofacuteliverfailureinmiceaswellasitstherapeuticpotential.MethodsWTmice（C57BL/6）wererandomly（randomnumber）allocatedtoinducingacuteliverfailurebylethaldosesofGalN/LPSinjectedi.p.Hepaticfunction，apoptosisofhepatocytesandhistologicalindexesweremeasuredatdifferentintervalsfollowingGalN/LPSchallenge.ThelevelsofextracellularhistonesweredeterminedbyusingELISAandWesternblotmethods.Meanwhile，GalN/LPS-treatedmicewereadministeredwithanti-histoneH3andanti-histoneH4neutralizedantibodies，respectively.ResultsAdministrationofGalN/LPStomicecausedacuteliverfailure，characterizedbysignificantelevationofplasmaALTlevelsandmassivehepatocyteapoptosisornecrosis.Allmicediedwithin9-12hours.ThelevelsofnucleosomesandextracellularhistonesH3andH4wereincreasedconsiderablyinatime-dependentmanner.ThesurvivalratesinGaIN/LPS-treatedmicewereimprovedremarkablyfollowingadministrationofanti-histoneH3andH4neutralizedantibodies（P=0.037，P=0.025），likelyduetothesignificantinhibitionofTNF-production.ConclusionsExtracellularhistonesareanimportantmediatorimplicatedinthepathogenesisofacuteliverfailure.Anti-histonesshowpromisingpotentialinthetreatmentofacuteliverfailure，whichdeservesfurtherinvestigationinthefuture. 　　【Keywords】Ext