Preconditioning: the molecular basis for protection from hepatic ischemia-reperfusion injury

当肝脏的血液供应被暂时切断(缺血)，然后恢复(再灌注)时，肝脏就会受到一种称为缺血再灌注(IR)损伤的过程的损害。这是肝脏手术中的一个主要问题，也是肝脏移植中的一个潜在问题；在保存供体肝脏准备放入受者体内后，它可能会经历一个类似的过程，称为保存损伤。我们现在对IR的发生有了很多了解，特别是通过在肝细胞内形成破坏性的氧自由基来启动细胞程序性死亡的过程，但预防或治疗IR损伤仍然是困难的。最近的一项突破是认识到，仅使肝脏遭受短期(5或10分钟)的缺血可以防止后期的长期缺血或IR。例如，在研究人员S的小鼠模型中，这种预适应具有60%到90%的保护性(取决于IR后的时间)。本项目旨在了解预适应如何保护肝脏免受IR损伤。我们的想法是，预适应产生有限数量的氧自由基，这些氧自由基启动细胞中调节某些保护性基因的信号通路。编码抗氧化剂和其他抗应激途径的基因可能很重要，但让细胞准备进入细胞周期并分裂成新细胞以再生肝脏的基因也很重要。相反，编程细胞死亡的基因可能会被关闭。这项研究的结果将是了解预适应如何保护肝脏免受缺血再灌注损伤的分子和细胞基础。这将使药物治疗得以设计出来，通过模拟预适应来预防这种常见而严重的肝脏损伤。

When the blood supply to the liver is cut off temporarily (ischemia) and later restored (reperfusion) the liver is damaged by a process called ischemia-reperfusion (IR) injury. This is a major problem during liver surgery and is also an underlying problem in liver transplantation; following storage of a donor liver ready for placing into the recipient it can undergo a similar process called preservation injury. We now understand a lot about how IR comes about, particularly by the formation of damaging oxygen radicals within liver cells to start a process of programmed cell death, but it remains difficult to prevent or treat IR injury. A recent breakthrough has been recognition that subjecting the liver to only a short period (5 or 10 minutes) of ischemia protects against a later period of prolonged ischemia or IR. In the investigator s mouse model, for example, such preconditioning was 60 to 90% protective (depending on the time after IR). This project seeks to understand how preconditioning works to protect the liver against IR injury. Our idea is that preconditioning generates a limited amount of oxygen radicals, and that these turn on signalling pathways in the cell that regulate certain protective genes. Genes that encode antioxidant and other anti-stress pathways are likely to be important, but so are genes that prepare the cell to enter the cell cycle and divide into new cells that regenerate the liver. Conversely, genes that program cell death may be turned off. The outcomes of this research will be to understand the molecular and cellular basis of how preconditioning protects against ischemia-reperfusion injury of the liver. This will allow drug treatments to be devised that, by simulating preconditioning, prevent this common and severe type of liver damage.