Hamada Tetsuhiro, Sato Ayuko, Hirano Tadamichi, Yamamoto Takashi, Son Gakuhei, Onodera Masayuki, Torii Ikuko, Nishigami Takashi, Tanaka Minoru, Miyajima Atsushi, Nishiguchi Shuhei, Fujimoto Jiro, Tsujimura Tohru
Department of Pathology, Hyogo College of Medicine, 1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan.
Am J Pathol. 2007 Sep;171(3):872-81. doi: 10.2353/ajpath.2007.060972. Epub 2007 Jul 19.
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.
为评估抑瘤素M（OSM）基因治疗在肝脏再生中的作用，我们研究了导入OSM cDNA是否能促进大鼠二甲基亚硝胺（DMN）损伤肝脏的再生。将包裹在日本血凝病毒包膜中的OSM cDNA反复注射到脾脏中，导致肝脏库普弗细胞中OSM蛋白的特异性表达，同时伴有体重、肝脏重量和血清白蛋白水平的增加，以及血清肝损伤参数（胆红素、天冬氨酸转氨酶和丙氨酸转氨酶）和血清纤维化参数（透明质酸）的降低。组织学检查显示，OSM基因治疗减少了中央小叶坏死和炎性细胞浸润，并增强了肝细胞增殖。OSM基因治疗抑制了肝细胞凋亡和纤维化。对DMN治疗前后进行OSM基因治疗的时间进程研究表明，该治疗不仅对促进DMN损伤的肝细胞再生有效，而且对预防后续DMN治疗引起的肝细胞毒性也有效。这些结果表明，OSM是肝细胞增殖和抗凋亡的关键介质，并提示OSM基因治疗作为预防和治疗手段，对肝损伤患者的治疗是有用的。
