Development of Therapentic Method to Promote Liver Regeneration by Modulating the Activin-Follistatin System

激活素A是肝细胞的自分泌生长抑制剂。当肝细胞受到生长因子刺激时，激活素A在G_1期中后期合成，并抑制DNA合成的起始。通过添加卵泡素（一种激活素结合蛋白）逆转激活素A的抑制作用，增加DNA合成。激活素A在肝部分切除后的残肝中表达。在切除70%肝后立即向大鼠门静脉注入卵泡抑素，可加速肝再生。DNA合成起始时间比对照大鼠早6小时。卵泡抑素处理大鼠的残肝重量和肝脏再生率显著提高。当静脉注射^<125>I-follistatin时，约10%的^<125>I-follistatin积聚在肝脏中。肝脏中卵泡抑素的含量在72小时内保持升高，但此后下降。在72小时注射促卵泡素加强剂可使肝内促卵泡素维持在高水平达120小时。当肝切除70%后静脉注射卵泡抑素，并在72小时注射加强剂时，通过DNA含量、残肝重量和肝再生率评估，肝再生明显增强。这些结果表明卵泡抑素促进部分肝切除术后肝再生的有效性。

Activin A is an autocrine growth inhibitor of hepatocytes. When hepatocytes were stimulated by growth factors, activin A is synthesized in the middle to late G_1 phase and inhibits initiation of DNA synthesis. Reversal of the inhibitory effect of activin A by adding follitatin, an activin-binding protein, augments DNA synthesis. Activin A is expressed in the remnant liver after partial hepatectomy. When follistatin was infused into the rat portal vein immediately after the 70% hepatectomy, liver regeneration was accelerated. Initiation of DNA synthesis was observed 6 hrs earlier than in control rats. The remnant liver weight and liver regeneration rate were significantly greater in follistatin-treated rats. When ^<125>I-follistatin administered intravenously, about 10% of the ^<125>I-follistatin was accumulated in the liver. The amount of follistatin in the liver remained elevated for up to 72 hrs but decreased thereafter. A booster shot of follistatin at 72 hrs maintained the intrahepatic follistatin at the high level for up to 120 hrs. When follistatin was infused intravenously after 70% hepatectomy followed by a booster shot at 72 hrs, the liver regeneration, as assese by the DNA content, remnant liver weight and liver regeneration rate, was significantly augmented. These results indicate the effectiveness of follistatin in promoting liver regeneration after partial hepatectomy.