Novel approach to control ischemia-reperfusion injury in small intestinal transplantation

控制小肠移植缺血再灌注损伤的新方法

• 批准号: 12307025
• 负责人: KITAJIMA Masaki
• 金额: $ 24.25万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 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-12307025/
• 关键词: small bowel transplantation; ischemia-reperfusion injury; mitogen activated protein kinase (MAPK); interleukin-1 (IL-1); tumor necrosis factor-α (INF-α); apoptosis; 虚血再灌流障害; interleukin-1(IL-1); 免疫抑制療法; MAP kinase

Because small intestine is one of the most susceptible organs to ischemia, ischemia-reperfusion injury is formidably limiting factor in small intestinal transplantation. By using rat small intestinal ischemia-reperfusion injury model, we demonstrated that TNF-α and IL-1β is produced in the rat small intesyinal ischemia-reperfusion injury and that the production can be reduced by the specific TNF-α and IL-1β inhibitor, attenuating the intestinal injury. Recently, mitogen-activated protein kinase (MARK) superfamily 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) and p38 induce cell apoptosis by various stimuli including ischemia. In addition, p38 acts as a key enzyme to produce IL-1 and TNF, suggesting these enzymes play a key role in ischemia-reperfusion Injury. In the present study, we investigated the pathophysiologic significance of JNK and p38 in rat small intestinal ischemia-reperfusion injury. Remarkable activation of JNK and p38 was shown in the injured small intestinal tissue after ischemia-reperfusion by using kinase assay. Immunohistochemistry of the intestinal tissue after reperfusion revealed that the activated p38 was mainly located in the epithelial cells of the villus tip, where TUNNEL positive apoptotic cells were present. Administration of LL-Z1640-2, a dual inhibitor of JNK and p38, effectively suppressed the activation of these enzymes, and reduced the number of apoptotic cells on villus tip, resulting that the mucosal morphology was well preserved. These results indicate that JNK and p38 play a key role in small intestinal ischemia-reperfusion injury, and that the simultaneous inhibition of these enzymes may provide a novel therapeutic approach to overcome ischemic damage in small intestinal transplantation.

由于小肠是最易受缺血影响的器官之一，缺血再灌注损伤是小肠移植的重要限制因素。在大鼠小肠缺血再灌注损伤模型上，我们证明了大鼠小肠缺血再灌注损伤时产生了肿瘤坏死因子-α和白介素1-β，而特异性的肿瘤坏死因子-α和白介素1β抑制剂可以减少这种产生，从而减轻肠道损伤。近年来，随着肿瘤坏死因子-α和白介素1-β的上游信号转导机制的报道，丝裂原活化蛋白激酶超家族受到广泛关注。尤其是c-jun氨基末端激酶(JNK)和p38可通过包括缺血在内的多种刺激诱导细胞凋亡。此外，p38是产生IL-1和肿瘤坏死因子的关键酶，提示这些酶在缺血再灌注损伤中起关键作用。本研究旨在探讨JNK和p38在大鼠小肠缺血再灌注损伤中的病理生理意义。用激活法检测，缺血再灌流后损伤的小肠组织中JNK和p38有明显的活化。再灌流后肠组织免疫组织化学显示，活化的p38主要定位于绒毛顶端的上皮细胞，可见隧道阳性的凋亡细胞。给予JNK和p38双重抑制剂LL-Z1640-2可有效抑制上述酶的激活，减少绒毛顶端细胞的凋亡，使黏膜形态得到较好的保存。这些结果表明JNK和p38在小肠缺血再灌注损伤中起关键作用，同时抑制这两种酶的表达可能为克服小肠移植中的缺血损伤提供新的治疗途径。

项目成果

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Yamamoto S. 等人：“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”《外科研究杂志》99. 134-141 (2001)。

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Minoru Tanabe：“小肠移植的现状”G.I.Research 9(1) (2001)。

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

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

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Masahiro Shinoda：“活体肝移植手术期间和术后的凝血和纤溶系统的变化及其管理”移植35（5）。