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Effect of portal hypertention by HGF gene therapy for liver cirrhosis

HGF基因治疗肝硬化门静脉高压症的疗效

基本信息

批准号：
11671197
负责人：
TAKEUCHI Masaharu
金额：
$ 2.3万
依托单位：
First Department of Surgery, Hyogo College of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671197/
关键词：
Liver cirrhosis gene therapy hepatocyte growth factor portal hypertension gene injection via hepatic artery 肝動脈注入

项目摘要

We performed gene therapy for liver cirrhosis. Liver cirrhosis was induced in rats and dogs by administrating dimethylnitrosamine (DIN) for 3 consecutive days a week. DMN is a hepatotoxic drug that causes liver cirrhosis. Hepatocyte death and parenchymal collapse occurred and fibrous component is evident by 4weeks. The naked HGF plasmid was injected into hepatic artery after cirrhosis has been established. Naked HGF plasmid does not contain any virus or lipid component. HGF showed maximum value from 7days to 14days after gene transfer. Azan-Mallory staining revealed that Regions of fibrosis markedly decreased and lobular architecture was well organized in HGF injected rats, but in MOCK rats, the formation of fibrous septa joining the central area and pseudolobule formation were evident. Photo-image analyzer measured the extent of fibrosis. Cirrhotic liver treated with HGF gene showed more than 50% less fibrosis than control cirrhotic liver. The proposed mechanism of therapeutic effect of HGF on liver cirrhosis is that HGF promotes MMPs producrtion and digests fiber tissue. We investigated expression of MMP-3 in the liver by Western blotting. The marked increase of this was observed in liver tissue of 7 days and 14 days after transfection of HGF gene. This therapeutic effect suppressed the portal pressure in HGF treated rats. HGF gene therapy improved the portal hypertension, Cirrhotic rat treated with HGF showed less portal pressure than MOCK transfected control cirrhotic rats.The naked HGF gene transfer into liver can treat rat liver cirrhosis and may be eventually translated into a useful clinical regimen for the treatment of patients with liver cirrhosis.

我们对肝硬化进行了基因治疗。用二甲基亚硝胺（DIN）每周连续3天诱发大鼠和狗肝硬化。DMN是一种肝毒性药物，可导致肝硬化。4周时出现肝细胞死亡和实质塌陷，纤维成分明显。肝硬化模型建立后，将裸HGF质粒经肝动脉注射。裸HGF质粒不含任何病毒或脂质成分。肝细胞生长因子在转基因后7 ~ 14天达到最大值。Azan-Mallory染色结果显示，HGF组肝纤维化程度明显减轻，小叶结构完整，而MOCK组肝纤维化程度明显减轻，小叶结构完整，纤维间隔连接中央区，假小叶形成。图像分析仪测量纤维化程度。HGF基因治疗的肝硬化肝纤维化比对照组减少50%以上。HGF治疗肝硬化的作用机制可能是通过促进MMPs的产生和纤维组织的增生。我们通过Western blotting检测了MMP-3在肝脏中的表达。在转染HGF基因后7天和14天的肝组织中观察到这一显著增加。这种治疗效果抑制肝细胞生长因子治疗大鼠的门静脉压力。HGF基因治疗可改善门脉高压，肝硬化大鼠门脉压力明显低于MOCK转染的对照组，表明HGF裸基因肝内转移可治疗大鼠肝硬化，并有望成为肝硬化治疗的一种有效的临床治疗方案。