Role of Cytokines in mediating of Ischemia/Reperfusion Injury in Liver.

细胞因子在介导肝脏缺血/再灌注损伤中的作用。

• 批准号: 08671424
• 负责人: SHIMIZU Koichi
• 金额: $ 1.47万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671424/
• 关键词: ischemia; reperfusion injury; cytokine; KF-kappaB; tyrosin kinase; JNK; apoptosis; liver; c-Jun N-terminal kinase; 肝虚血再灌流障害; TNF-α; IL-6; チロシンキナーゼ阻害剤; ゲニステイン

One of the most important complications after organ transplantation is graft damage caused by ischemia/reperfusion injury. The details of the mechanisms underlying organ injury under ischemia and reperfusion are not yet understood. We investigated the role of cytokines in mediating of ischemia/reperfusion injury and the intracellular signal transduction that modulates cytokine production.The results from in-vitro experiments have shown that hypoxia induces the activation of NF-kappaB and tyrosine kinase inhibitors inhibits NF-kappaB activation by hypoxia. And the results from experiments using a mouse model for hepatic ischemia and reperfusion have shown that inflammatory cytokies affect liver injury following ischemia/reperfusion, and that pretreatment with a tyrosine kinase inhibitor, genistein, suppresses ischemia/reperfusion injury of the liver. Furthermore, it was also shown that JNK (c-Jun N-terminal kinase) was activated following hepatic ischemia and reperfusion. Interestingly, the activation of JNK and the number of apoptotic cells increased by shorter period of ischemia rather than longer period.These results suggest that inhibition of cytokine production can suppress ischemia/reperfusion injury, and that JNK activation and apoptosis after short period of ischemia may play a protective role in tissue subjected to ischemia and reperfusion.

器官移植后最重要的并发症之一是由缺血/再灌注损伤引起的移植物损伤。在缺血和再灌流条件下器官损伤的具体机制尚不清楚。我们研究了细胞因子在介导缺血/再灌注损伤中的作用以及调节细胞因子产生的细胞内信号转导。体外实验结果表明，低氧诱导核因子-kappaB的激活，酪氨酸激酶抑制剂抑制低氧诱导的核因子-kappaB的激活。使用小鼠肝脏缺血和再灌注模型的实验结果表明，炎性细胞因子影响缺血/再灌注后的肝脏损伤，而酪氨酸激酶抑制剂金雀异黄素预处理可抑制肝脏的缺血/再灌注损伤。此外，还发现肝脏缺血再灌流后JNK(c-jun氨基末端激酶)被激活。有趣的是，JNK的活性和凋亡细胞数随缺血时间的缩短而增加，提示抑制细胞因子的产生可以抑制缺血/再灌注损伤，JNK的激活和缺血后的细胞凋亡可能对缺血再灌注损伤的组织具有保护作用。

项目成果

Yamamoto, S., Shimizu, K., et al.: "Genistein suppresses cellular injury following hepatic ischemia/reperfusion." Transplantation Proceedings. 28・(2). 1111-1115 (1996)

Yamamoto, S., Shimizu, K., et al.：“金雀异黄素抑制肝缺血/再灌注后的细胞损伤。” 28·(2) (1996)。

Muraoka, K., Shimizu, K, et al.: "Hypoxia,but not reoxygenation,induces interleukin 6 gene expression through NF-κB activation." Transplantation. 63・(2). 466-470 (1997)

Muraoka, K., Shimizu, K, et al.：“缺氧而非复氧，通过 NF-κB 激活诱导白细胞介素 6 基因表达。”63·(2)。

Onishi, I., Tani, T., et al.: "Activation of c-Jun N-terminal kinase during ischemia and reperfusion in mouse liver." FEBS Letters. 420. 201-204 (1997)

Onishi, I.、Tani, T. 等人：“小鼠肝脏缺血和再灌注期间 c-Jun N 末端激酶的激活。”

Onishi,I., Shimizu,K., et.al.: "Activation of c-Jun N-terminal kinase during ischemia and reperfusion in mouse liver." FFBS Letters. 4・20. 201-204 (1997)

Onishi,I., Shimizu,K., et.al.：“小鼠肝脏缺血和再灌注过程中 c-Jun N 末端激酶的激活”，FFBS Letters 4·20 (1997)。

Onishi, I., Shimizu, K., et al.: "Activation of c-Jun N-terminalkinase during ischemia and reperfusion in mouse liver." FEBS Letters. 420. 201-204 (1997)

Onishi, I.、Shimizu, K. 等人：“小鼠肝脏缺血和再灌注期间 c-Jun N 末端激酶的激活。”