Ozawa Satoru, Uchiyama Kazuhisa, Nakamori Mikihito, Ueda Kentaro, Iwahashi Makoto, Ueno Hikaru, Muragaki Yasuteru, Ooshima Akira, Yamaue Hiroki
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
Surgery. 2006 Apr;139(4):563-73. doi: 10.1016/j.surg.2005.10.003.
In a cirrhotic liver, the regenerative ability and specific functions are impaired; a hepatic resection increases the possibility of postoperative liver failure. Hepatocyte growth factor (HGF) stimulates liver regeneration, accelerates restoration of hepatic function, and improves fibrosis. A truncated type II transforming growth factor-beta receptor (TbetaTR), which specifically inhibits TGF-beta signaling as a dominant-negative receptor, appears to prevent the progression of liver fibrosis. We demonstrated the therapeutic efficacy of adenovirus-mediated HGF and TbetaTR gene transduction after partial hepatectomy for liver cirrhosis.
Rats were treated with dimethylnitrosamine for 3 weeks, and they all had severe cirrhosis. After partial hepatectomy (10%), we injected adenovirus expressing bacterial beta-galactosidase (AdLacZ), adenovirus expressing a truncated type II TGF-beta receptor (AdTbetaTR), adenovirus expressing hepatocyte growth factor (AdHGF), or AdTbetaTR + AdHGF into the portal vein, which was followed by an additional 2-week dimethylnitrosamine treatment.
On histologic examination, fibrotic tissue had decreased in the livers of the AdTbetaTR + AdHGF-treated rats compared with rats that were treated by AdLacZ, AdTbetaTR alone, and AdHGF alone. Liver function, which included serum levels of alanine aminotransferase, improved significantly in AdTbetaTR + AdHGF-treated rats compared with all other groups. The number of hepatocytes that were positive for proliferating-cell nuclear antigen was greater (P < .05) in AdHGF alone and AdTbetaTR + AdHGF-treated rat livers than in AdLacZ- and AdTbetaTR-treated rats. All AdTbetaTR + AdHGF-treated rats survived >60 days, and AdTbetaTR + AdHGF treatment markedly improved the survival rate after a partial hepatectomy.
Our results suggest that the combination of HGF and TbetaTR gene therapy may increase the possibility of hepatectomy in a cirrhotic liver by improving fibrosis, hepatic function, and hepatocyte regeneration.
在肝硬化肝脏中，再生能力和特定功能受损；肝切除会增加术后肝衰竭的可能性。肝细胞生长因子（HGF）可刺激肝脏再生，加速肝功能恢复，并改善纤维化。截短的II型转化生长因子-β受体（TbetaTR）作为显性负性受体特异性抑制TGF-β信号传导，似乎可阻止肝纤维化进展。我们证明了腺病毒介导的HGF和TbetaTR基因转导在肝硬化部分肝切除术后的治疗效果。
用二甲基亚硝胺处理大鼠3周，使其均患有严重肝硬化。在部分肝切除（10%）后，我们将表达细菌β-半乳糖苷酶的腺病毒（AdLacZ）、表达截短的II型TGF-β受体的腺病毒（AdTbetaTR）、表达肝细胞生长因子的腺病毒（AdHGF）或AdTbetaTR + AdHGF注入门静脉，随后再用二甲基亚硝胺处理2周。
组织学检查显示，与单独接受AdLacZ、AdTbetaTR和AdHGF处理的大鼠相比，AdTbetaTR + AdHGF处理的大鼠肝脏纤维化组织减少。与所有其他组相比，AdTbetaTR + AdHGF处理的大鼠肝功能（包括血清丙氨酸转氨酶水平）显著改善。单独使用AdHGF和AdTbetaTR + AdHGF处理的大鼠肝脏中增殖细胞核抗原阳性的肝细胞数量比AdLacZ和AdTbetaTR处理的大鼠更多（P <.05）。所有接受AdTbetaTR + AdHGF处理的大鼠存活时间超过60天，AdTbetaTR + AdHGF处理显著提高了部分肝切除术后的存活率。
我们的结果表明，HGF和TbetaTR基因治疗联合应用可能通过改善纤维化、肝功能和肝细胞再生，增加肝硬化肝脏行肝切除术的可能性。
