title: Protective action of hepatocyte growth factor for acute liver injury caused by D-galactosamine in transgenic mice.
abstract: Hepatocyte growth factor (HGF) has been reported to be a potent mitogen for hepatocytes in vivo and in vitro. Recent reports have shown that HGF has cytoprotective actions in acute liver injury models, but its mechanisms remain to be resolved. In the present study, we investigated whether HGF could work as an anti-hepatitis agent for acute liver injury caused by D-galactosamine (D-GalN) using transgenic (TG) mice expressing HGF in hepatocytes, compared with wild-type (WT) mice of their siblings. After administration of 3 g/kg body weight of D-GalN, elevated serum transaminase levels and severe liver damage that were observed in WT mice were significantly improved in TG mice. In TG mice, the percentage of proliferating cell nuclear antigen (PCNA)-positive hepatocytes was high at 0 hours after D-GalN treatment, and increased at 24 hours. The percentage of PCNA-positive cells in WT mice was very low at 0 hours and 24 hours after treatment, but increased at 48 hours. To clarify the mechanisms via which HGF acts, we measured hepatic HGF and prostaglandin E2 (PGE2) contents after D-GalN administration by an enzyme immunoassay. Total hepatic HGF contents, which were composed of murine (endogeneous) and human (derived from transgene) HGF, in TG mice were higher than those in WT mice at 0, 12, and 24 hours after administration of 3 g/kg body weight of D-GalN. Hepatic PGE2 contents in TG mice were also significantly higher than those in WT mice. Hepatic PGE2 contents had a positive correlation with total HGF contents at both 12 hours and 24 hours after the treatment. Moreover, an administration of 0.5 microg of anti-HGF antibody into the portal vein suppressed hepatic PGE2 contents of mice, compared with saline-injected mice in acute liver injury. Anti-PGE2 antibody administration caused more severe liver damage than saline solution. A survival rate of TG mice that were given 6 g/kg body weight of D-GalN-a lethal dose of D-GalN-was improved compared with WT mice. These results provided direct evidences that HGF worked as an anti-hepatitis agent against acute liver injury caused by D-GalN, and that this action might be exerted through accelerated hepatic PGE2 production.
authors.affiliation: Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Okano
authors.forename: G
authors.initials: G
authors.lastname: Shiota
authors.forename: H
authors.initials: H
authors.lastname: Kawasaki
mesh_terms: D000208:Acute Disease; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005688:Galactosamine / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000235:genetics; D011169:Portal Vein; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D013194:Staining and Labeling; D016019:Survival Analysis
chemical_list: D000906:Antibodies; D018809:Proliferating Cell Nuclear Antigen; D017228:Hepatocyte Growth Factor; D005688:Galactosamine; D000410:Alanine Transaminase; D015232:Dinoprostone