Chen Yi, Hozawa Shigenari, Sawamura Sadaaki, Sato Shinkichi, Fukuyama Naoto, Tsuji Chizuko, Mine Tetsuya, Okada Yasunori, Tanino Ryuzaburo, Ogushi Yoichi, Nakazawa Hiroe
Department of Physiology, School of Medicine, Tokai University, Bohseidai, Isehara, Kanagawa 259-1193, Japan.
Biochem Biophys Res Commun. 2005 Jan 7;326(1):45-51. doi: 10.1016/j.bbrc.2004.10.202.
The role of inducible nitric oxide synthase (iNOS) in the progression of fibrosis during nonalcoholic steatohepatitis remains to be elucidated. This study examined the role of iNOS in the progression of fibrosis during steatohepatitis by comparing iNOS knockout (iNOS(-/-)) and wild-type (iNOS(+/+)) mice that were fed a high-fat diet. Severe fatty metamorphosis developed in the liver of iNOS(+/+) and iNOS(-/-) mice. Fibrotic changes were marked in iNOS(-/-) mice. Gelatin zymography showed that pro MMP-2 and pro MMP-9 protein expressions were more highly induced in iNOS(+/+) mice than in iNOS(-/-) mice. Active forms of MMP-2 and MMP-9 were clearly present only in the liver tissue of iNOS(+/+) mice. In situ zymography showed strong gelatinolytic activities in the liver tissue of iNOS(+/+) mice, but only spotty activity in iNOS(-/-)mice. iNOS may attenuate the progression of liver fibrosis in steatohepatitis, in part by inducing MMP-2 and MMP-9 expression and augmenting their activity.
诱导型一氧化氮合酶（iNOS）在非酒精性脂肪性肝炎纤维化进展中的作用仍有待阐明。本研究通过比较喂食高脂饮食的iNOS基因敲除（iNOS(-/-)）小鼠和野生型（iNOS(+/+)）小鼠，探讨了iNOS在脂肪性肝炎纤维化进展中的作用。iNOS(+/+)和iNOS(-/-)小鼠肝脏均出现严重的脂肪变性。iNOS(-/-)小鼠有明显的纤维化改变。明胶酶谱分析显示，与iNOS(-/-)小鼠相比，iNOS(+/+)小鼠中前MMP-2和前MMP-9蛋白表达的诱导程度更高。MMP-2和MMP-9的活性形式仅在iNOS(+/+)小鼠的肝组织中明显存在。原位酶谱分析显示，iNOS(+/+)小鼠肝组织中有很强的明胶酶解活性，而iNOS(-/-)小鼠中只有散在的活性。iNOS可能部分通过诱导MMP-2和MMP-9的表达并增强其活性，来减轻脂肪性肝炎中肝纤维化的进展。
