Resarch on trial to suppress surgical in cirrhotic liver by modulating activation of hepatic sinusoidal cells.

首先，采用硫代乙酰胺灌胃8周建立大鼠肝硬变模型。在这个模型中，已经被证明在肝脏中拮抗eNOS的小窝蛋白-1被过度表达。在这项研究中，我们决定检测HMG-CoA还原酶抑制剂对肝脏缺血/再灌注损伤的影响，因为已有报道它们调节小窝蛋白-1的功能。在我们的实验中，我们使用普伐他汀，我们观察了普伐他汀对正常大鼠肝脏I/R损伤的影响，但与对照组相比，普伐他汀预处理并不能抑制这种损伤。我们还检测了该药对肝硬变大鼠肝脏的影响。在肝硬变患者中，肝脏I/R后血清转氨酶水平明显低于正常肝脏。普伐他汀治疗组大鼠心肌I/R损伤较对照组有抑制趋势，但无统计学意义。结果提示，肝硬变肝脏I/R损伤机制可能与正常肝…不同。因此，为了阐明正常肝和肝硬变大鼠肝脏I/R损伤机制的差异，本研究以大鼠正常肝和肝硬变大鼠肝组织中提取的mRNA为模板，用DNA芯片技术检测了正常肝和肝硬变大鼠肝脏I/R损伤相关基因表达的差异。结果表明，与细胞周期和应激蛋白相关的几个基因表达上调。尽管需要对这些基因进行精确的检测，但调控这些基因将是抑制肝硬变I/R损伤的替代靶点。由于普伐他汀对I/R损伤没有显示出抑制作用，我们尝试了其他方法来操纵肝窦细胞，使用ROCK/Rho激酶抑制剂Y-27632和诱导肝脏中血红素加氧酶-1的吡咯烷二氨基氨基甲酸酯(PDTC)。前者改善正常大鼠肝脏微循环，抑制肝脏I/R损伤和内毒素肝损伤，后者具有扩张肝窦、抑制正常肝脏I/R损伤的作用。这些结果表明，调节肝窦细胞是一种新的可能的方法来减少肝脏I/R损伤，即使在肝硬变中也是如此。我们相信上述结果将为开发抑制肝硬变肝窦循环障碍和I/R损伤的新方法奠定基础。较少

First, we established the cirrhotic rat model by orally administrating thioacetamide for 8 weeks. In this model, caveolin-1, already shown to antagonize eNOS in the liver, was overexpressed. In this research, we decided to examine the effect of HMG-CoA reducase inhibitors on hepatic ischemia/reperfusion injury because they have been reported to modulate the function of caveolin-1. In our experiments, we used pravastatin.We examined the effect of pravastatin on hepatic I/R injury in normal rat liver, but pre-treatment of pravastatin did not suppress the injury compared with the control. We also examined the effect in the cirrhotic rat liver. In the cirrhotic liver, serum transaminase levels after hepatic I/R were much lower than in normal liver. The I/R injury in the pravastatin-treated group tended to be suppressed compare with the control, but it was not significant. The results suggested that the mechanism of hepatic I/R injury in cirrhotic liver might be different from in normal liv … More er.So, to elucidate the difference of mechanism of hepatic I/R injury between normal liver and cirrhotic liver, the difference of the gene expression between them was examined with, DNA array technique using mRNA extracted from normal rat liver and cirrhotic rat liver. The result showed that several genes related with cell cycle and stress proteins were up-regulated. Although the precise examination of those genes is needed, modulating those genes would be alternative targets for suppressing I/R injury in cirrhotic liver.Because pravastatin did not show the suppressive effect on I/R injury, we tried other ways for manupulation of sinusoidal cells using Y-27632, a ROCK/Rho kinase inhibitor, and pyrrolidine dithinocarbamate (PDTC), which induced heme oxygenase-1 in the liver. The former improved hepatic micro-circulation and suppressed hepatic I/R injury in normal rat liver and endotoxic liver injury, and the latter showed dilatative effect of hepatic sinusoids and suppressed I/R injury in normal liver. Those results suggest that modulating sinusoidal cells be a novel possible approach to minimize hepatic I/R injury, even in cirrhotic liver.We believe the results above altogether will be the basis for developing novel approach to suppress the disturbance of sinusoidal circulation and I/R injury in cirrhotic liver. Less