The hepatic sympathetic nerve plays a critical role in preventing Fas induced liver injury in mice
The hepatic sympathetic nerve plays a critical role in preventing Fas induced liver injury in mice
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DOI：
10.1136/gut.2004.058818
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发表时间：
2005-07-01
期刊：
影响因子：
24.5
通讯作者：
Kubo, C
中科院分区：
文献类型：
--
作者：
Chida, Y;Sudo, N;Kubo, C
背景资料：虽然以前的研究表明，肝交感神经控制着肝脏的各种生理功能，但该神经在肝损伤中的作用尚未阐明。目的：本研究的目的是阐明该神经的作用，基于我们新开发的选择性去除肝交感神经活动的技术。主题和方法：对雄性C57 BL/6小鼠进行肝交感神经去神经手术。此后，对小鼠静脉内施用0.25或0.35mg/g体重的Fas激动剂抗体Jo-2，之后评估暴发性肝炎的死亡率。在肝脏中的细胞凋亡也检查了两个末端脱氧核苷酸转移酶介导的dUTP缺口末端标记和caspase-3 assay.Results：死亡率在交感神经切除小鼠明显高于在假手术小鼠给药后的Jo-2。这一结果也得到了细胞凋亡数据的支持，其中交感神经切除的肝脏与假手术肝脏相比，在Jo-2治疗后，凋亡肝细胞的数量和半胱天冬酶-3活性显著升高。此外，预处理去甲肾上腺素剂量依赖性抑制肝交感神经切除诱导的死亡率增加后，Jo-2注射。在Jo-2治疗后1小时和2小时，交感神经切除小鼠肝脏中FLICE抑制蛋白、Bcl-xL和Bcl-2的抗凋亡蛋白水平显著低于假手术动物。此外，白细胞介素6补充剂量依赖性抑制肝交感神经切除术诱导的死亡率增加后，Jo-2 treatment.Conclusions：这些结果表明，从肝交感神经释放的去甲肾上腺素起着关键作用，在保护肝脏从Fas介导的暴发性肝炎，可能通过机制，包括抗凋亡蛋白和白细胞介素6。
Background: Although previous studies have shown that the hepatic sympathetic nerve controls various physiological functions in the liver, the role of this nerve in liver injury has yet to be clarified.Aims: The purpose of this study was to elucidate the role of this nerve, based on our newly developed technique for selectively removing the activities of the hepatic sympathetic nerve.Subjects and methods: Male C57BL/6 mice were operated on for hepatic sympathetic denervation. Thereafter, mice were intravenously administered 0.25 or 0.35 mg/g weight of the Fas agonist antibody, Jo-2, after which mortality by fulminant hepatitis was evaluated. Apoptosis in the liver was also examined by both terminal deoxynucleotidyl transferase mediated dUTP nick end labelling and caspase-3 assay.Results: Mortality in sympathectomised mice was significantly higher than that in sham operated mice following administration of Jo-2. This result was also supported by apoptosis data in which sympathectomised livers exhibited a significant elevation in the number of apoptotic hepatocytes and caspase-3 activity after Jo-2 treatment compared with sham operated livers. Moreover, pretreatment with norepinephrine dose dependently inhibited the hepatic sympathectomy induced increase in mortality after Jo-2 injection. Antiapoptotic protein levels of FLICE inhibitory protein, Bcl-xL, and Bcl-2 in the liver were significantly lower in sympathectomised mice at one and two hours following Jo-2 treatment than in sham operated animals. In addition, interleukin 6 supplementation dose dependently suppressed the hepatic sympathectomy induced increase in mortality after Jo-2 treatment.Conclusions: These results suggest that norepinephrine released from the hepatic sympathetic nerve plays a critical role in protecting the liver from Fas mediated fulminant hepatitis, possibly via mechanisms including antiapoptotic proteins and interleukin 6.