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

通过调节肝窦细胞的活化来抑制肝硬化肝手术的试验研究。

• 批准号: 14370388
• 负责人: HASEGAWA Suguru
• 金额: $ 8.7万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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-14370388/
• 关键词: hepatectomy; cirrhosis; ischemia; reperfusion injury; hepatic sinusoidal cells; hepatic sinusoidal blood flow; molecular chaperon

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

首先，采用硫代乙酰胺灌胃8周的方法建立大鼠急性中毒模型。在该模型中，已经显示在肝脏中拮抗eNOS的小窝蛋白-1过表达。在这项研究中，我们决定检查HMG-CoA还原酶抑制剂对肝脏缺血/再灌注损伤的影响，因为据报道它们可以调节小窝蛋白-1的功能。在我们的实验中，我们使用普伐他汀，我们研究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，普伐他汀预处理不能抑制损伤。我们还研究了在大鼠肝脏中的作用。肝I/R后血清转氨酶水平明显低于正常肝。普伐他汀治疗组I/R损伤较对照组有减轻趋势，但无统计学意义。结果提示，急性肝缺血再灌注损伤的机制可能与正常肝不同。 ...更多信息 因此，为了阐明正常肝和肝硬化大鼠肝I/R损伤机制的差异，本研究采用DNA微阵列技术，从正常大鼠肝和肝硬化大鼠肝中提取mRNA，检测它们之间基因表达的差异。结果表明，与细胞周期和胁迫蛋白相关的多个基因表达上调。由于普伐他汀对缺血再灌注损伤无抑制作用，我们尝试了其他方法，用ROCK/Rho激酶抑制剂Y-27632和诱导血红素氧合酶-1的吡咯烷二硫代氨基甲酸酯（PDTC）来操纵肝窦细胞。前者改善肝微循环，抑制正常肝和内毒素性肝损伤的肝I/R损伤;后者改善肝血窦，抑制正常肝的I/R损伤。这些结果提示，调控肝窦细胞是一种新的可能的减轻肝I/R损伤的方法，即使在缺血性肝损伤中也是如此，我们相信上述结果将为开发新的抑制肝窦循环障碍和I/R损伤的方法奠定基础。少

项目成果

Iimuro Y: "Delivery of matrix metalloproteinase-1 attenuates established liver fibrosis in the rat."Gastroenterology. 124(2). 445-458 (2003)

Iimuro Y：“给予基质金属蛋白酶-1 可减轻大鼠已形成的肝纤维化。”胃肠病学。

Harada N: "Inactivation of the small GTPase Rac1 protects the liver from ischemia/reperfusion injury in the rat."Surgery. 134(3). 480-491 (2003)

Harada N：“小 GTP 酶 Rac1 的失活可保护大鼠肝脏免受缺血/再灌注损伤。”手术。

Nishio T: "Increased expression of collagenase in the liver induces hepatocyte proliferation with cytoplasmic accumulation of beta-catenin in the rat."J Hepatol.. 38(4). 468-475 (2003)

Nishio T：“肝脏中胶原酶表达的增加会诱导大鼠肝细胞增殖，β-连环蛋白在细胞质中积累。”J Hepatol.. 38(4)。

Shimahara Y: "Significance of serum type N collagen level of hepatectomized patients with chronic liver damage."World J Surg.. 26(4). 451-456 (2002)

Shimahara Y：“慢性肝损伤肝切除患者血清 N 型胶原水平的意义。”World J Surg. 26(4)。

Nitta T: "Myoglobin gene expression attenuates hepatic ischemia reperfusion injury"J Surg Res.. 110(2). 322-331 (2003)

Nitta T：“肌红蛋白基因表达减轻肝缺血再灌注损伤”J Surg Res.. 110(2)。