Intravenous injection of an adenovirus encoding hepatocyte growth factor results in liver growth and has a protective effect against apoptosis

Background: Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotrop ic cytokine with mitogenic, motogenic and morphogenic effects for a wide va riety of cells. Previous studies have reported that the in vivo infusion in normal, untreated mice of recombinant HGF results in low levels of DNA syn thesis and liver proliferation. In this study, we examined whether liver re generation could be obtained by the in vivo injection of a recombinant aden oviral vector encoding human HGF (Ad.CMV.rhHGF) in normal, intact mice. Materials and Methods: C57BL/6 mice were infused intravenously with doses i ncreasing from 1 to 4 x (11) particles of the recombinant human HGF (rhHGF) adenoviral vector or with a control virus encoding Escherichia coli beta-g alactosidase (Ad.CMV.lacZ). At day 5, mice were sacrificed and evaluated fo r the presence of hepatocyte mitogenesis and liver regeneration (5-bromo-2' -deoxyuridine (BrdU) assays and liver weight determination) and for the pre sence of liver damage (serum alanine amino-transferase (ALT) measurements a nd TUNEL assays). Results: In vivo administration of rhHGF stimulated DNA synthesis of hepato cytes and liver weight in a dose-dependent fashion. The maximal effect was seen after the infusion of 3 x 10(11) particles which resulted at day 5 in >130% increase in relative liver mass with little cytopathic effect. In con trast, administration of the lacZ adenoviral vector caused little hepatocyt e replication, but induced high levels of serum ALT (similar to 3 times hig her than the rhHGF vector) and significant apoptotic cell death. Conclusions: This study shows that a single injection of Ad.CMV.rhHGF alone is able to induce in vivo and in a very short period of time, robust DNA s ynthesis and liver proliferation in normal mice without liver injury or par tial hepatectomy. This recombinant adenoviral vector has a lower toxicity t han the control lacZ adenovirus. This suggests that HGF may have a protecti ve effect against adenovirus-induced pathology.