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LIVER PROTECTION AGAINST ISCHEMIAJREPERFUSION INJURY BY ISCHEMIC PRECONDITIONING

通过缺血预适应保护肝脏免受缺血再灌注损伤

基本信息

批准号：
14570452
负责人：
ARAI Masahiro
金额：
$ 2.24万
依托单位：
THE UNIVERSITY OF TOKYO
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570452/
关键词：
ISCHEMIA REPERFUSION INJURY ISCHEMIC PRECONDITIONING LIVER TRANSPLANTATION

项目摘要

Brief periods of ischemia followed by reperfusion render tissues resistant against subsequent prolonged ischemia, a phenomenon called ischemic preconditioning. We previously showed that ischemic preconditioning decreased sinusoidal endothelial cell injury and Kupffer cell activation after ischemia/reperfusion with the consequence of improved survival of liver transplant recipients. Although cardioprotective effect of ischemic preconditioning disappears within a few hours, the effect appears again 24-48 hours after ischemic preconditioning, which is called late preconditioning. Since the late preconditioning shows various cardioprotective effects and lasts longer than the early preconditioning, its clinical efficacy is recently drawing attention. Thus we set out to investigate whether late preconditioning works in the liver or not, and to elucidate, if it works, its mechanisms. Ischemia/reperfusion injury was induced in rat livers by clamping hepatic artery and portal vein into the median and left lobes. To evaluate hepatocyte injury, serum activities of ALT and LDH were determined. At first, we decided appropriate ischemic time and the timing of evaluation in the preliminary experiments. Ischemic preconditioning was performed by clamping the hepatic artery and portal vein into the median and left lobes for 10 minutes followed by 10 minutes reperfusion. Ischemic preconditioning reduced liver injury after 60 minutes ischemia and 180 minutes reperfusion. When ischemia/reperfusion injury was induced at 2 hours after ischemic preconditioning, the hepatoprotective effect disappeared. However, ischemia/reperfusion injury induced 24 hours after ischemic preconditioning was reduced compared to no preconditioning group. We are now launching the experiments using adenosine antagonists to investigate the contribution of adenosine receptors to the development of late preconditioning.

短暂的缺血和再灌注使组织对随后的长期缺血具有抵抗力，这种现象称为缺血预适应。我们之前表明，缺血预处理可减少缺血/再灌注后的肝窦内皮细胞损伤和库普弗细胞活化，从而提高肝移植受者的存活率。虽然缺血预适应的心脏保护作用在数小时内消失，但在缺血预适应后24-48小时，该作用再次出现，称为晚期预适应。由于晚期预处理显示出多种心脏保护作用，并且比早期预处理持续时间更长，因此其临床疗效最近引起了人们的关注。因此，我们着手研究晚期预处理是否在肝脏中起作用，并阐明其机制（如果有效）。通过将肝动脉和门静脉夹入中叶和左叶，在大鼠肝脏中诱导缺血/再灌注损伤。为了评估肝细胞损伤，测定了 ALT 和 LDH 的血清活性。首先，我们在初步实验中确定了合适的缺血时间和评估时机。通过将肝动脉和门静脉夹入正中叶和左叶10分钟，然后再灌注10分钟来进行缺血预处理。缺血预处理可减少 60 分钟缺血和 180 分钟再灌注后的肝损伤。缺血预处理后2小时诱发缺血/再灌注损伤时，保肝作用消失。然而，与无预处理组相比，缺血预处理后24小时诱导的缺血/再灌注损伤减少。我们现在正在启动使用腺苷拮抗剂的实验，以研究腺苷受体对晚期预处理发展的贡献。