The role of MARK in hepatic ischemia-reperfusion injury

MARK在肝缺血再灌注损伤中的作用

• 批准号: 12671173
• 负责人: TANABE Minoru
• 金额: $ 2.43万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671173/
• 关键词: ischemia-reperfusion injury; liver transplantation; c-Jun N-terminal kinase (JNK); tumor necrosis factor-α (TNF-α); microcirculation; c-Jun N-terminal kinase(JNK); 肝障害; MAP kinase; 虚血再潅流障害

Patients with end-stage liver disease in Japan still depend on living-donor liver transplantation, since cadaveric organ donation is extremely rare. Because ischemia-reperfusion injury of the graft organ is inevitable in transplantation, control of ischemic injury enable us to use the organ safely from unsalable or nonheartbeating donor, leading to the improvement of organ shortage. We have been demonstrated the key role of tumor necrosis factor (TNF) and interleukin-1 in ischemia-reperfusion injury of the liver and small intestine. Recently, mitogen-activated protein kinase (MAPK) super family has been widely noticed as upupstream signal transduction mechanisms for TNF-α and IL-1β have been reported. Especially, c-Jun N-terminal kinase (JNK) induce cell apoptosis by various stimuli including ischemia, suggesting these enzymes play a key role in ischemia reperfusion injury. We investigated the activation of JNK during hepatic ischemia-reperfusion injury in the rat model.Remarkable hemrrahgic necrosis was shown in the reperfused liver after 60-minute warm ischemia, and the mean serum AST increased over 2000 IU/L at 180 minutes after reperfusion, indicating that severe liver damage was induced. In vivo microfluorograph showed remarkable increase in leukocyte-endothelium interaction in sinusoids and venules of the reperfused liver. After reperfusion, tissue and serum TNF-α level increased over 6 folds, and tissue JNK activity increased by 12.5 folds, compared to the value before ischemia. These results suggest that JNK may play some role in the mechnism of ischemia reperfusion injury.

日本的终末期肝病患者仍然依赖活体肝移植，因为尸体器官捐献极为罕见，因为移植器官的缺血再灌注损伤是不可避免的，控制缺血性损伤使我们能够使用器官。安全地来自滞销或无心跳的供体，从而改善器官短缺。我们已经证明了肿瘤坏死因子（TNF）和白细胞介素-1在缺血再灌注损伤中的关键作用。近年来，丝裂原激活蛋白激酶（MAPK）超家族作为TNF-α和IL-1β的上游信号转导机制而受到广泛关注，特别是c-Jun N末端激酶（JNK）。通过包括缺血在内的各种刺激诱导细胞凋亡，表明这些酶在缺血再灌注损伤中发挥关键作用。我们研究了大鼠肝脏缺血再灌注损伤期间 JNK 的激活。热缺血60分钟后，再灌注肝脏出现明显的出血性坏死，再灌注180分钟后，血清AST平均升高超过2000 IU/L，体内显微荧光显示，肝脏出现严重损伤。再灌注肝脏的血窦和小静脉中的白细胞-内皮相互作用 再灌注后，组织和血清 TNF-α 水平。与缺血前相比，JNK活性增加了6倍以上，组织JNK活性增加了12.5倍，这些结果表明JNK可能在缺血再灌注损伤的机制中发挥一定作用。

项目成果

Tanabe M: "Intraportal infusion therapy as a novel approach to adult ABO-incompatible liver transplantation"Transplantation. (in press).

Tanabe M：“门静脉内输注疗法作为成人 ABO 不相容肝移植的一种新方法”移植。

田辺稔: "ドナープール拡大の工夫:生体肝移植におけるドナープールの拡大"消化器外科. 25(3). 283-289 (2002)

Minoru Tanabe：“扩大供体库的努力：活体肝移植中供体库的扩展”25（3）283-289（2002）。

島津元秀: "肝虚血・再灌流障害におけるnitric oxide(NO)の役割"G.I.Research. 9(4). 363 (2001)

Motohide Shimazu：“一氧化氮（NO）在肝缺血/再灌注损伤中的作用”G.I.Research 9（4）363（2001）。

Yamamoto S: "The role of tumor necrosis factor-α and interleukin-1β in ischemia-reperfusion injury of the rat small intestine. "J Surg Res. (in press).

Yamamoto S：“肿瘤坏死因子-α 和白细胞介素-1β 在大鼠小肠缺血再灌注损伤中的作用。”J Surg Res。

Tanabe M, et al.: "Intraportal infusion therapy as a novel approach to adult ABO-incompatible liver transplantation"Transplantation. (in press).

Tanabe M 等人：“门静脉内输注疗法是成人 ABO 不相容肝移植的一种新方法”移植。