Published online before print July 19, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.060972

Accepted for publication June 5, 2007.

Article

Oncostatin M Gene Therapy Attenuates Liver Damage Induced by Dimethylnitrosamine in Rats

Tetsuhiro Hamada^*, Ayuko Sato^*, Tadamichi Hirano, Takashi Yamamoto, Gakuhei Son, Masayuki Onodera^*, Ikuko Torii^*, Takashi Nishigami^*, Minoru Tanaka, Atsushi Miyajima, Shuhei Nishiguchi^¶, Jiro Fujimoto, and Tohru Tsujimura^*@

From the Departments of Pathology* and Surgery and Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine,^¶ Hyogo College of Medicine, Hyogo; the Department of Clinical Laboratory, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; and the Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan

^@ To whom correspondence should be addressed. E-mail: tohru{at}hyo-med.ac.jp.

	Abstract

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.