survival after hepatic injury induced by carbon tetrachlo-When 1 mg 125 I-follistatin was administered into a rat ride. 7 In addition, hepatocyte growth factor augmented liver intravenously, radioactivity levels in serum decreased regeneration after partial hepatectomy. 7 Nevertheless, the rapidly. Analysis with a biexponential equation showed efficacy of hepatocyte growth factor is modest. that the initial half-life and the terminal half-life were Activin A is a dimeric protein with a variety of biological 4.0 and 130.8 minutes, respectively. After 2 hours of infusion, approximately 9% of the follistatin infused re-actions in many types of cells. 8,9 It belongs to the transmained in the liver, which was much more than that in forming growth factor b supergene family and it modulates kidney, spleen, pancreas, intestine, or lung. Autoradioggrowth and differentiation in many tissues. Studies in our raphy of the liver obtained at 24 hours of infusion relaboratory have provided evidence that activin A is an autovealed that numerous grains were located in parenchycrine growth inhibitor in hepatocytes. 10 Activin A is produced mal cells. Radioactivity of 125 I-follistatin in the liver in cultured rat parenchymal hepatocytes stimulated by epiremained elevated until 72 hours and declined markedly dermal growth factor or hepatocyte growth factor. Messenger thereafter. When a booster shot of 125 I-follistatin was ad-RNA expression and the release of mature protein are markministered at 72 hours, radioactivity in the liver at 120 edly increased in mid-to late-G 1 phase. The growth inhibition hours was markedly increased compared with that in caused by activin A is significant because a blockade of the rats that received a single shot of 125 I-follistatin. We then action of endogenous activin A leads to enhanced DNA synexamined the effect of intravenous infusion of follistatin thesis. 11 Activin A is also induced in vivo after partial hepaon liver regeneration after hepatectomy of 70%. Immeditectomy. 10 Low levels of the messenger RNA for the b A -subately after the hepatectomy, either 1 mg follistatin or unit of activin have been detected in the liver; these saline was infused intravenously. In some rats, a booster disappeared 3 hours after partial hepatectomy and are markshot was infused at 72 hours. After 120 hours of hepatecedly increased 20 hours after hepatectomy. When follistatin, tomy of 70%, remnant liver weight, liver regeneration which binds activin and blocks its action, 11,12 is infused into rate, and DNA content were significantly (P Γ΅ .05) higher the portal vein immediately after hepatectomy of 70%, DNA in rats that received a booster shot of follistatin at 72 is synthesized several hours earlier than in control rats and hours than those in control rats. These results indicate liver regeneration is significantly augmented. 13 A single adthat follistatin administered intravenously accumulates ministration of follistatin is much more effective than several in the liver and promotes liver regeneration after partial administrations of hepatocyte growth factor in promoting hepatectomy. (HEPATOLOGY 1996;24:361-366.) liver regeneration. 7,13 Follistatin provides a potential therapeutic approach to promoting liver regeneration because it Augmentation of liver regeneration, with an artificial supspecifically blocks autocrine growth inhibitor. In the present port to maintain liver function necessary for survival, would study, we investigated whether the intravenous administrabe beneficial for the treatment of fulminant hepatic failure tion of follistatin effectively promoted liver regeneration after caused by viral infection and hepatic toxins. 1 As well, massive partial hepatectomy. We studied the tissue distribution of hepatectomy to resect liver tumors can be performed safely follistatin infused intravenously and determined an effective if the growth of the remnant liver is promoted effectively. means of maintaining the follistatin content in the liver. The Various attempts have been made to promote liver regeneraresults indicate that intravenous follistatin is effective in protion. Farivar et al. 2 have reported that the infusion of insulin moting liver regeneration after hepatectomy of 70%. and glucagon decreased mortality in murine hepatic failure by stimulating liver regeneration. However, the effectiveness
Methods
of the infusion of insulin and glucagon has not been confirmed in humans. [3][4][5] The roles of various growth factors in the regu-Experimental Animals. All studies were performed according to lation of hepatocyte growth have been elucidated. 1,6 The adthe American Association for the Accreditation of Laboratory Animal ministration of growth factors should therefore promote liver Care guidelines. Male Wistar rats obtained from Imai Animal Com- regeneration. Hepatocyte growth factor increases murine pany (Saitama, Japan) were fed with regular laboratory chow (Orien- tal Mouse Food, Tokyo, Japan) and kept in a temperature-controlled (24 { 1ΠC) and artificially illuminated room (light on from 7 AM to 7 PM). Food and water were withdrawn from the animals for 3 hours Abbreviation: PCNA, proliferating cell nuclear antigen.