Kaido T, Yoshikawa A, Seto S, Yamaoka S, Sato M, Ishii T, Imamura M
Department of Surgery and Surgical Basic Science, Kyoto University School of Medicine, Japan.
Hepatology. 1998 Sep;28(3):756-60. doi: 10.1002/hep.510280323.
In a cirrhotic liver, the regenerative ability and specific functions are so impaired that excessive resection easily complicates postoperative liver dysfunction, which frequently leads to life-threatening multiple-organ failure. Hepatocyte growth factor (HGF), first identified as the most potent stimulator of DNA synthesis in primary hepatocytes, not only stimulates liver regeneration, but also accelerates hepatic function, improves fibrosis, and protects liver cells against injury. Therefore, we investigated the efficacy of preoperative portal branch ligation (PBL) (which can induce compensatory hypertrophy of the unaffected lobes) combined with a continuous HGF supply in the performance of extensive hepatectomy in cirrhotic rats. Cirrhosis was induced by intraperitoneal injections of dimethylnitrosamine (DMN) three times per week for 3 weeks. Five days after the last injection, when 70% hepatectomy is lethal, the rats underwent portal ligation of the left lateral and median branches (corresponding to approximately 70% of the total volume of the liver). Simultaneously, they were continuously treated with either recombinant human HGF (rhHGF) or vehicle from an intraperitoneally implanted osmotic pump. Four days after the portal ligation, the occluded lobes were resected. The HGF treatment rapidly increased both the wet weight of the unoccluded lobes and the hepatocellular DNA synthesis. The blood chemical analysis indicated that HGF significantly suppressed the posthepatectomy liver dysfunction. Most importantly, the HGF treatment markedly improved the survival rate of the rats at 48 hours after the major hepatectomy. In conclusion, PBL combined with a continuous HGF supply makes extensive hepatectomy possible in cirrhotic rats, mainly by promoting the hypertrophy of the unaffected lobes.
在肝硬化肝脏中，其再生能力和特定功能严重受损，过度切除极易导致术后肝功能障碍，进而常常引发危及生命的多器官衰竭。肝细胞生长因子（HGF）最初被确定为原代肝细胞中最有效的DNA合成刺激因子，它不仅能刺激肝脏再生，还能加速肝功能恢复、改善纤维化并保护肝细胞免受损伤。因此，我们研究了术前门静脉分支结扎（PBL）（可诱导未受影响肝叶的代偿性肥大）联合持续给予HGF在肝硬化大鼠广泛肝切除术中的疗效。通过每周腹腔注射三次二甲基亚硝胺（DMN），持续3周来诱导肝硬化。在最后一次注射后5天，此时70%肝切除是致命的，对大鼠进行左外侧和中间分支的门静脉结扎（约占肝脏总体积的70%）。同时，通过腹腔植入的渗透泵，它们持续接受重组人HGF（rhHGF）或载体治疗。门静脉结扎4天后，切除闭塞的肝叶。HGF治疗迅速增加了未闭塞肝叶的湿重和肝细胞DNA合成。血液化学分析表明，HGF显著抑制了肝切除术后的肝功能障碍。最重要的是，HGF治疗显著提高了大鼠在大肝切除术后48小时的存活率。总之，PBL联合持续给予HGF使肝硬化大鼠进行广泛肝切除成为可能，主要是通过促进未受影响肝叶的肥大来实现的。
