Inhibition of transforming growth factor β prevents progression of liver fibrosis and enhances hepatocyte regeneration in dimethylnitrosamine-treated rats
Inhibition of transforming growth factor β prevents progression of liver fibrosis and enhances hepatocyte regeneration in dimethylnitrosamine-treated rats
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DOI：
10.1053/jhep.2000.9109
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发表时间：
2000-08-01
期刊：
影响因子：
13.5
通讯作者：
Ueno, H
中科院分区：
文献类型：
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作者：
Nakamura, T;Sakata, R;Ueno, H
我们研究了抗转化生长因子β（TGF-β）分子干预是否可以阻止大鼠肝纤维化的进展。为了以特定方式阻断 TGF-β 作用，我们制备了表达截短的 II 型 TGF-β 受体（AdT beta-TR）的腺病毒，它作为显性失活受体特异性抑制 TGF-β 信号传导。我们还使用表达细菌 β-半乳糖苷酶 (AdLacZ) 的腺病毒作为对照腺病毒。用二甲基亚硝胺（DMN）治疗大鼠3周；然后静脉注射一次AdT beta-TR、AdLacZ或生理盐水，然后再进行3周的DMN治疗。基因转移后1周时截短型受体与野生型受体在mRNA水平上的比率为15，3周时为10。免疫组化分析显示，截短受体主要表达于包括肝星状细胞在内的间隔细胞。通过组织学、羟脯氨酸含量和血清透明质酸水平评估，肝纤维化在额外的 3 周 DMN 治疗期间有所进展。然而，在感染 AdT beta-TR 的大鼠中，纤维化仍保持在仅接受 DMN 3 周的大鼠中所见的水平。所有 AdT beta-TR 治疗的大鼠均存活，而注射 AdLacZ 或盐水的 DMN 治疗的大鼠则因肝功能障碍而死亡。在 AdT beta-TR 处理的大鼠肝脏中，电子显微镜显示：1）Disse 间隙中细胞外基质蛋白的积累减少； 2）再生肝细胞； 3）富含脂肪滴的“静止”肝星状细胞，我们的结果表明TGF-β在肝纤维化的进展中发挥着关键作用，并表明抗TGF-β干预应该对已经形成的纤维化肝脏具有治疗作用，不仅可以抑制纤维化，还可以促进肝细胞再生。
We investigated whether anti-transforming growth factor beta (TGF-beta) molecular intervention can halt the progression of liver fibrosis in rats. To block TGF-beta action in a specific manner, we prepared an adenovirus expressing a truncated type II TGF-beta receptor (AdT beta-TR), which specifically inhibits TGF-beta signaling as a dominant-negative receptor. We also used an adenovirus expressing bacterial beta-galactosidase (AdLacZ) as a control adenovirus. Rats were treated with dimethylnitrosamine (DMN) for 3 weeks; then, AdT beta-TR, AdLacZ, or saline was intravenously applied once, followed by an additional 3-week DMN treatment. The ratio between the truncated receptor and the wild-type receptor at the mRNA level was 15 at 1 week and 10 at 3 weeks after gene transfer. Immunohistostaining analysis showed that the truncated receptor was expressed mainly in septal cells including hepatic stellate cells. Liver fibrosis, as assessed by histology, hydroxyproline content, and the serum level of hyaluronic acid, progressed during the additional 3-week DMN treatment, However, in rats infected with AdT beta-TR, the fibrosis remained at the level seen in rats given DMN for only 3 weeks. All AdT beta-TR-treated rats remained alive, whereas DMN-treated rats infused with either AdLacZ or saline died of liver dysfunction. In the livers of AdT beta-TR-treated rats, electron microscopy showed: 1) less accumulation of extracellular matrix proteins in the Disse's spaces; 2) regenerated hepatocytes; and 3) fat droplet-rich "quiescent" hepatic stellate cells, Our results demonstrate that TGF-beta plays a critical role in the progression of liver fibrosis, and suggest that anti-TGF-beta intervention should be therapeutic in already-established fibrotic livers, not only by suppressing fibrosis, but by facilitating hepatocyte regeneration.