Combination gene therapy of HGF and truncated type II TGF-β receptor for rat liver cirrhosis after partial hepatectomy
Combination gene therapy of HGF and truncated type II TGF-β receptor for rat liver cirrhosis after partial hepatectomy
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DOI：
10.1016/j.surg.2005.10.003
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发表时间：
2006-04-01
期刊：
影响因子：
3.8
通讯作者：
Yamaue, H
中科院分区：
文献类型：
--
作者：
Ozawa, S;Uchiyama, K;Yamaue, H
背景资料。在肝硬变中，再生能力和特异性连接受损；肝切除增加了术后肝功能衰竭的可能性。肝细胞生长因子(HGF)刺激肝脏再生，加速肝功能恢复，改善纤维化。一种截短型H型转化生长因子-β受体(T-β受体)，作为显性负性受体，特异性地抑制转化生长因子-β信号转导，似乎可以预防。肝纤维化的进展。我们论证了腺病毒介导的肝细胞生长因子和Tβ受体基因转导对肝硬变部分切除后的治疗效果。二甲基亚硝胺治疗3周后，大鼠均出现严重的肝硬变。肝部分切除(10%)后，门静脉注射表达细菌β-半乳糖苷酶(AdLacZ)的腺病毒(AdLacZ)、表达截短的II型转化生长因子受体的腺病毒(ADT-βTR)、表达肝细胞生长因子(AdHGF)的腺病毒(AdHGF)或AdT-β-TR+AdHGF，再加用二甲基亚硝胺治疗2周。组织学检查，纤维组织减少。在ADTβ-TR+AdHGF处理组的肝脏中。与AdLacZ、ADTβ受体单独和AdHGF单独治疗的大鼠进行比较。与ALL相比，ADTβTR+AdHGF治疗组大鼠的肝功能(包括血清丙氨酸氨基转移酶水平)显著改善。其他团体。AdHGF单独和AdT-β-TR+AdHGF处理的大鼠肝细胞增殖细胞核抗原阳性细胞数明显多于AdLacZ和AdT-β-TR处理的大鼠(P<；0.05)。ADT-β-TR+AdHGF组大鼠均存活60天，且ADT-β-TR+AdHGF组能显著提高大鼠肝部分切除后的存活率。我们的结果表明，HGF和Tβ受体基因联合治疗可能通过改善肝纤维化、肝功能和肝细胞再生来增加肝硬变患者切除肝的可能性。
Background. In a cirrhotic liver, the regenerative abilily and specific junctions 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 H transforming growth factor-beta receptor (T beta TR), 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 T beta TR gene transduction after partial hepatectomy for liver cirrhosis.Methods. 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 (AdT beta TR), adenovirus expressing hepatocyte growth factor (AdHGF), or AdT beta TR + AdHGF into the portal vein, which was followed by an additional 2-week dimethylnitrosamine treatment.Results. On histologic examination, fibrotic tissue had decreased. in the livers of the AdT beta TR + AdHGF-treated. rats compared with rats that were treated by AdLacZ, AdT beta TR alone, and AdHGF alone. Liver function, which included serum levels of alanine aminotransferase, improved significantly in AdT beta TR + 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 AdT beta TR + AdHGF-treated rat livers than in AdLacZ and AdT beta TR-treated rats. All AdT beta TR + AdHGF-treated rats survived > 60 days, and AdT beta TR + AdHGF treatment markedly improved the survival rate after a partial hepatectomy.Conclusion. Our results suggest that the combination of HGF and T beta TR gene therapy may increase the possibility of hepatectomy in a cirrhotic liver by improving fibrosis, hepatic function, and hepatocyte regeneration.