ANTI-HEPATOCYTE GROWTH-FACTOR ANTIBODY INHIBITS HEPATOCYTE PROLIFERATION DURING LIVER-REGENERATION

In vitro studies have shown hepatocyte growth factor (HGF) to be a pot ent mitogen for hepatocytes. Direct evidence of a mitogenic role in vi vo was sought by inhibiting HGF activity, using continuous administrat ion of neutralizing antibody to rats which had a stimulus for liver re generation. Alzet osmotic mini-pumps, administering a constant supply of anti-HGF monoclonal antibody (clone D9), were inserted intraperiton eally into male Wistar rats; an irrelevant isotypical antibody was adm inistered to controls. Forty-five animals received an intragastric bol us of 40 per cent carbon tetrachloride (CCl4) and groups of three test and control animals were killed at 24 h intervals for 7 days. Treatme nt with anti-HGF monoclonal antibody significantly inhibited the level s of immunodetectable HGF in the sera of rats following CCl4 administr ation. In comparison with controls, hepatocyte proliferation as assess ed by bromodeoxyuridine labelling in anti-HGF-treated animals was sign ificantly inhibited at 24 h (P<0.001), 48 h (P<0.001), and 96 h (P<0.0 5) post-CCl4 administration. In contrast, sinusoidal cell proliferatio n was not significantly different from controls at any time point. Inh ibition of the parenchymal proliferative response to acute CCl4-induce d liver injury by the in vivo neutralization of HGF provides direct ev idence that this growth factor plays an important role in liver regene ration following necrosis. (C) 1998 John Wiley & Sons, Ltd.