Effect of HB-EGF on liver regeneration in vovo and its application as a therapeutic agent.

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We have reported that heparin-binding EGF-like growth factor(HB-EGF) is a potent mitogen of hepatocytes in vitro.The level of HB -EGF mRNA in regenerating rat liver increases rapidly after a partial hepatectomy.In vitro study showed that HB-EGF induces the expression of HGF and TGF-alpha in non-parenchymal cells and hepatocytes, respectively.These results indicated that HB-EGF may play an important role in liver regeneration.In this study, we investigated the plasma HB-EGF levels in patients after partial hepatectomy using enzyme-linked immunosorbent assay.In patients who underwent gross hepatectomy, plasma HB-EGF levels increased, reaching maximal levels approximately 5 to 7 days after surgery, which indicated that HB-EGF may be involved in liver regeneration in human.We also investigated the effect of administration HB-EGF to mice on proliferation of hepatocyte in vivo.Recombinant HB-EGF were administered intravenously to the normal mice for 4 times at 2h-interval.Proliferation of hepatocyte were determined as labeling index of BrdU.Activation of NE-kB and STAT-3 were studied using gel shift assay.The labeling index is 300-fold higher in HB-EGF administered mice than that of controls.In vivo administration of HB-EGF activated NF-kB and STAT-3 in the liver. The induction of HGF were observed in HB-EGF-administered mice liver.In summary, in vivo administration of HB-EGF stimulated liver regeneration in normal mice liver, which indicated that HB-EGF could be a therapeutic agent for liver regeneration.