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

当肝脏的血液供应暂时中断（缺血），然后恢复（再灌注）时，肝脏就会受到缺血再灌注（IR）损伤。这是肝脏手术中的一个主要问题，也是肝移植的一个潜在问题；在供体肝脏储存准备放入受体后，它可以经历一个类似的过程，称为保存损伤。我们现在对IR是如何产生的了解很多，特别是通过在肝细胞内形成破坏性的氧自由基来启动程序性细胞死亡的过程，但仍然很难预防或治疗IR损伤。最近的一项突破已经认识到，使肝脏仅进行短时间（5或10分钟）缺血可以防止后期的长时间缺血或IR。例如，在研究者的小鼠模型中，这种预处理具有60%至90%的保护作用（取决于IR后的时间）。该项目旨在了解预处理如何保护肝脏免受IR损伤。我们的想法是，预处理会产生有限数量的氧自由基，这些自由基会打开细胞中调节某些保护性基因的信号通路。编码抗氧化和其他抗应激途径的基因可能很重要，但准备细胞进入细胞周期并分裂成再生肝脏的新细胞的基因也很重要。相反，控制细胞死亡的基因可能会被关闭。本研究的结果将是了解预处理如何保护肝脏缺血再灌注损伤的分子和细胞基础。这将允许设计药物治疗，通过模拟预处理，防止这种常见和严重类型的肝损伤。

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.