细胞外组蛋白在急性肝衰竭小鼠中变化.docVIP

细胞外组蛋白在急性肝衰竭小鼠中变化 　　【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9～12 h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 　　Changes of extracellular histones in mice with acute liver failure and its therapeutic potentialWEN Tao， GOU Chun-yan， LU Jing， LIU Yan， PIAO Zheng-fu， LI Feng， CHEN De-xi. Beijing Institute of Hepatology， Beijing Youan Hospital Affiliated with Capital Medical University， Beijing 100069， China 　　Corresponding author： CHEN De-xi， Email： dexi09@ 　　【Abstract】Objective To investigate the changes of extracellular histones during the course of acute liver failure in mice as well as its therapeutic potential.Methods WT mice （C57BL/6） were randomly （random number） allocated to inducing acute liver failure by lethal doses of GalN/LPS injected i.p. Hepatic function， apoptosis of hepatocytes and histological indexes were measured at different intervals following GalN/LPS challenge. The levels of extracellular histones were determined by using ELISA and Western blot methods. Meanwhile， GalN/LPS-treated mice were administered with anti-histone H3 and anti-histone H4 neutralized antibodies， respectively. Results Administration of GalN/LPS to mice caused acute liver failure， characterized by significant elevation of plasma ALT levels and massive hepatocyte apoptosis or necrosis. All mice died within 9-12 hours. The levels of nucleosomes and extracellular histones H3 and H4 were increased considerably in a time-dependent manner. The survival rates in GaIN/LPS-treated mice were improved remarkably following administration of anti-histone H3 and H4 neutralized antibodies （P=0.037，P=0.025）， likely due to the significant inhibition of TNF-production. Conclusions Extracellular hist