Prevention of hepatic ischemia-reperfusion injury by gene transfer of IкB antisense and its application to liver transplantation

IкB反义基因转染预防肝缺血再灌注损伤及其在肝移植中的应用

• 批准号: 13671342
• 负责人: SHIMAZU Motohide
• 金额: $ 2.56万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671342/
• 关键词: IкB; NFкB; antisence; genetransfer; ischemia-reperfusion injury; liver transplantation; IkB; NFkB; 肝虚血再灌流傷害

NFкB is a transcriptional factor which plays a major role in production of inflammatory cytokines and regulation of apoptosis. However, it is still unclear whether up-regulation of NFкB has a cytoprotective effect or not in hepatic ischemia-reperfusion injury. We already constructed a recombinant adenovirus vector expressing a truncated form of the inhibition protein IкB (Adex IкB), and demonstrated that transfer of Adex IкB inhibited NFкB activation and aggravated hepatic ischemia-reperfusion injury in rats. In the present study, we tried to construct Adex IкB antisense suppressing IкB production and investigated the effect of IкB antisense gene transfer to NFкB activation and ischemia-reperfusion injury. In vitro, amount of IкB was not decreased in cultured cells infected Adex IкB antisense, although IкB antisense cDNA was detected by RT-PCR. In hepatic ischemia-reperfusion model in rats, administration of Adex IкB antisense did not attenuate hepatic injury compared to the control group

NF B是一种转录因子，在炎症细胞因子的产生和细胞凋亡的调节中起主要作用。然而，上调NF B表达是否对肝脏缺血再灌注损伤具有细胞保护作用尚不清楚。我们已经构建了表达抑制蛋白I B截短型（Adex I B）的重组腺病毒载体，并证明Adex I B的转移抑制了NF B的活化，加重了大鼠肝脏缺血再灌注损伤。本研究试图构建抑制I B生成的Adex I B反义基因，并探讨I B反义基因转染对NF B活化及缺血再灌注损伤的影响。体外培养的细胞经Adex I B反义核酸感染后，I B的表达量无明显下降，但RT-PCR检测到I B反义cDNA的表达。在大鼠肝缺血再灌注模型中，与对照组相比，Adex I B反义核酸的给药没有减轻肝损伤

项目成果

Harada H, Wakabayashi G, et al.: "Transfer of Interleukin-1 receptor antagonist gene into rat liver abrogates hepatic ischemia-reperfusion injury"Transplantation. 74. 1434-1441 (2002)

Harada H、Wakabayashi G 等人：“将白细胞介素 1 受体拮抗剂基因转移至大鼠肝脏可消除肝缺血再灌注损伤”移植。

Kawachi S, Shimazu M, Wakabayashi G, et al.: "Biliary complications in adult living donor liver transplantation with duct-to-duct hepaticocholedochostomy or Roux-en-Y hepaticojejunostomy biliary"Surgery. 132. 48-56 (2002)

Kawachi S、Shimazu M、Wakabayashi G 等人：“采用导管至导管肝胆总管切开术或 Roux-en-Y 肝空肠吻合术进行胆道成人活体肝移植的胆道并发症”手术。

Obara H, Shimazu M, et al.: "Overexpression of Truncated IκBα Induces TNF-α-Dependent Apoptosis in Human Vascular Smooth Muscle Cells"Arteriosclerosis, Thrombosis, and Vascular Biology. 19. 2198-2204 (2000)

Obara H、Shimazu M 等人：“截短的 IκBα 的过度表达会诱导人血管平滑肌细胞中的 TNF-α 依赖性凋亡”动脉硬化、血栓形成和血管生物学 19。2198-2204 (2000)。

Shinoda M, Shimazu M, et al.: "Tumor necrosis factor suppression and microcirculatory disturbance amelioration in ischemia/reperfusion injury of rat liver after ischemic preconditioning"J Gastroenterol Hepatol. 17. 1211-1219 (2002)

Shinoda M，Shimazu M，等：“缺血预处理后大鼠肝脏缺血/再灌注损伤中的肿瘤坏死因子抑制和微循环障碍改善”J Gastroenterol Hepatol。

篠田 昌宏, 島津 元秀, ほか: "肝虚血再灌流障害に対するischemic preconditioning(IPC)とその機序"侵襲と免疫. 9. 18-23 (2000)

Masahiro Shinoda、Motohide Shimazu 等：“缺血预处理（IPC）及其肝脏缺血再灌注损伤的机制”《侵袭与免疫学》9. 18-23 (2000)。