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.

在日本，终末期肝病患者仍然依赖活体肝移植，因为尸体器官捐赠非常罕见。由于移植器官的缺血再灌注损伤是不可避免的，控制缺血损伤使我们能够安全地使用来自滞销或无心跳供体的器官，从而改善器官短缺的状况。肿瘤坏死因子（TNF）和白细胞介素-1（IL-1）在肝脏和小肠缺血再灌注损伤中的作用已被证实。近年来，随着TNF-α和IL-1β上游信号转导机制的研究报道，丝裂原活化蛋白激酶（MAPK）超家族受到广泛关注。尤其是c-Jun氨基末端激酶（JNK）在缺血等多种刺激下诱导细胞凋亡，提示这些酶在缺血再灌注损伤中起着重要作用。在大鼠肝缺血再灌注损伤模型上，观察JNK的激活情况，发现热缺血60分钟后再灌注肝脏出现明显的出血性坏死，再灌注180分钟时血清AST平均升高超过2000 IU/L，提示肝损伤严重。在体显微荧光照片显示再灌注肝血窦和小静脉中白细胞-内皮细胞相互作用显著增加。再灌注后，组织和血清TNF-α水平较缺血前升高6倍以上，组织JNK活性较缺血前升高12.5倍。提示JNK可能在缺血再灌注损伤中起一定作用。

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.: "Various efforts to expand donor pool in living-donor liver transplantation"Shokakigeka. 25 (3). 283-289 (2002)

Tanabe M 等人：“扩大活体肝移植供体库的各种努力”Shokakigeka。