Oncostatin M gene therapy attenuates liver damage induced by dimethylnitrosamine in rats.
To assess the usefulness of oncostatin M (osm) gene therapy in liver regeneration, we examined whether the introduction of OSM cDNA enhances the regeneration of livers damaged by dimethylnitrosamine (DMN) in rats. Repeated injection of OSM cDNA enclosed in hemagglutinating virus of Japan envelope into the spleen resulted in the exclusive expression of OSM protein in Kupffer cells of the liver, which was accompanied by increases in body weight, liver weight, and serum albumin levels and the reduction of serum liver injury parameters (bilirubin, aspartate aminotransferase, and alanine aminotransferase) and a serum fibrosis parameter (hyaluronic acid). Histological examination showed that osm gene therapy reduced centrilobular necrosis and inflammatory cell infiltration and augmented hepatocyte proliferation. The apoptosis of hepatocytes and fibrosis were suppressed by osm gene therapy. Time-course studies on osm gene therapy before or after DMN treatment showed that this therapy was effective not only in enhancing regeneration of hepatocytes damaged by DMN but in preventing hepatic cytotoxicity caused by subsequent treatment with DMN. These results indicate that OSM is a key mediator for proliferation and anti-apoptosis of hepatocytes and suggest that osm gene therapy is useful, as preventive and curative means, for the treatment of patients with liver damage.
Hamada
Tetsuhiro
T
Department of Pathology, Hyogo College of Medicine, 1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan.
Sato
Ayuko
A
Hirano
Tadamichi
T
Yamamoto
Takashi
T
Son
Gakuhei
G
Onodera
Masayuki
M
Torii
Ikuko
I
Nishigami
Takashi
T
Tanaka
Minoru
M
Miyajima
Atsushi
A
Nishiguchi
Shuhei
S
Fujimoto
Jiro
J
Tsujimura
Tohru
T
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004128:Dimethylnitrosamine / Q000633:toxicity*; D015316:Genetic Therapy; D006131:Growth Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008107:Liver Diseases / Q000235:genetics / Q000628:therapy; D008297:Male; D053683:Oncostatin M / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006131:Growth Inhibitors; D053683:Oncostatin M; D004128:Dimethylnitrosamine