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Contribution to the extended hepatectomy by the modulation of endoplasmic reticulum stress-induced cell death

通过调节内质网应激诱导的细胞死亡对扩大肝切除术的贡献

基本信息

批准号：
15591401
负责人：
HATANO Etsuro
金额：
$ 2.18万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Blocking of death receptor-induced and mitochondrial apoptotic pathways is insufficient to inhibition of hepatic ischemia/reperfusion injury and cholestatic injury. Therefore, we focus on endoplasmic reticulum(ER) stress-induced apoptotic pathway, so-called third apoptotic pathway, in these liver injuries. Our aim of this study is to clarify the role of ER stress-induced apoptotic signaling pathway in mouse hepatic ischemia/reperfusion and cholestatic injury. Ischemia/reperfusion injury was induced by ischemia in 70% of the liver for 90 minutes followed by reperfusion in C57BL6 mice. Cholestatic liver injury was induced by ligation of the bile duct in C57BL6 mice. RT-PCR demonstrated the elevation of mRNA levels in GADD 153 immediately after reperfusion and in GRP78 12 hours after reperfusion. Western blotting showed the enhanced expression of GADD153 3 hours after reperfusion. The mRNA levels in GRP78 and caspase-12 were elevated 12 hours after reperfusion. The expression of GRP78 and GADD153 were elevated in both mRNA and protein levels 24 hours after bile duct-ligation. In both models, the decrease in procaspase-12 and the increase in the number of apoptotic cell death were shown by the Western blotting and TUNEL assay, respectively. In conclusion, this study is a first report showing that GADD153 induced by ER stress is involved in apoptosis in hepatic injury after reperfusion and obstructive jaundice. However, the specific role of GADD153 in these hepatic injuries is not clear. Now we are conducting the additional experiment using GADD153 knock out mice.

阻断死亡受体诱导的凋亡途径和线粒体凋亡途径不足以抑制肝脏缺血/再灌注损伤和胆汁淤积性损伤。因此，我们将重点放在内质网（ER）应激诱导的凋亡途径，所谓的第三凋亡途径，在这些肝损伤。本研究旨在探讨内质网应激诱导的细胞凋亡信号通路在小鼠肝脏缺血再灌注损伤和胆汁淤积性损伤中的作用。在C57 BL 6小鼠中，通过在70%的肝脏中缺血90分钟，然后再灌注来诱导缺血/再灌注损伤。通过结扎C57 BL 6小鼠的胆管诱导胆汁淤积性肝损伤。RT-PCR显示GADD 153在再灌注后即刻和GRP 78在再灌注后12小时的mRNA水平升高。Western blotting显示再灌注3 h后GADD 153表达增强。再灌注12 h后GRP 78和caspase-12的mRNA水平升高。胆管结扎后24 h，GADD 153和GRP 78在mRNA和蛋白水平上均表达升高。在这两种模型中，蛋白质印迹和TUNEL法分别显示了半胱天冬酶原-12的减少和凋亡细胞死亡数量的增加。总之，本研究是第一个报告表明，GADD 153诱导的ER应激参与细胞凋亡的肝损伤后再灌注和梗阻性黄疸。然而，GADD 153在这些肝损伤中的具体作用尚不清楚。现在我们正在使用GADD 153敲除小鼠进行额外的实验。

项目成果

期刊论文数量（58）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Akt activation protects rat liver from ischemia/reperfusion injury

DOI：
10.1016/j.jss.2004.04.016
发表时间：
2004-10-01
期刊：
JOURNAL OF SURGICAL RESEARCH
影响因子：
2.2
作者：
Harada, N;Hatano, E;Yamaoka, Y
通讯作者：
Yamaoka, Y

Inhibition of tumor necrosis factor-induced apoptosis in transgenic mouse liver expressing creatine kinase.

抑制表达肌酸激酶的转基因小鼠肝脏中肿瘤坏死因子诱导的细胞凋亡。

DOI：
发表时间：
2004
期刊：
Liver Int 24巻・4号
影响因子：
0
作者：
N.Koizumi;H.Suetsugu;Koizumi N;Suetsugu H;K.Taura;DM.Black;H.Terajima;N.Harada;E.Hatano
通讯作者：
E.Hatano

Myoglobin Gene Expression Attenuates Hepatic Ischemia Reperfusion Injury.

肌红蛋白基因表达减轻肝脏缺血再灌注损伤。

DOI：
发表时间：
2003
期刊：
J Surg Res 110巻・2号
影响因子：
0
作者：
N.Koizumi;H.Suetsugu;Koizumi N;Suetsugu H;K.Taura;DM.Black;H.Terajima;N.Harada;E.Hatano;Taura K;Black D;Terajima H;Harada N;Hatano E;N.Harada;RF.Schwabe;E.Hatano;T.Nitta
通讯作者：
T.Nitta

Blocking of PI3K / Akt pathway enhances apoptosis induced by SN-38, an active form of CPT-11, in human hepatoma cells.

阻断 PI3K/Akt 通路可增强 SN-38（CPT-11 的一种活性形式）在人肝癌细胞中诱导的细胞凋亡。