Two novel antifibrotics, HOE 077 and Safironil, modulate stellate cell activation in rat liver injury: differential effects in males and females.
Two novel antifibrotics, HOE 077 and Safironil, modulate stellate cell activation in rat liver injury: differential effects in males and females.
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发表时间：
1998
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通讯作者：
Yuan-Jen Wang;Shaoqiong Wang;Martin;Bickel;V. Guenzler;Gerl;D. Bissell
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作者：
Yuan-Jen Wang;Shaoqiong Wang;Martin;Bickel;V. Guenzler;Gerl;D. Bissell
损伤环境中的肝窦周星状细胞经历活化，获得成肌纤维细胞样表型。在这种状态下，它们是纤维化中胶原蛋白和相关蛋白的主要来源。本研究评价了两种新型抗纤维化化合物HOE 077和Safironil的作用机制，这两种化合物被设计为胶原蛋白合成的竞争性抑制剂。通过给予四氯化碳在大鼠中诱导纤维化，并以I型胶原mRNA或平滑肌α-肌动蛋白的水平监测活化。研究了雄性和雌性大鼠。在完整肝脏中，星状细胞活化而非胶原蛋白合成被证明是HOE 077和Safionil的靶点。在培养中，药物不仅阻止了星状细胞的激活，而且加速了它们的失活。它们在含肝细胞的共培养物中的有效性并不比在纯星状细胞培养物中更高，表明不需要HOE 077的代谢转化。有趣的是，来自雌性的细胞的反应大于雄性细胞的反应，从而得出星状激活是性二态的结论。这一发现可能与慢性病毒性肝炎中纤维化进展较慢以及女性肝细胞癌发生率低于男性的观察结果有关。
The perisinusoidal stellate cells of the liver in an injury milieu undergo activation, acquiring a myofibroblast-like phenotype. In this state, they are the principal source of collagen and related proteins in fibrosis. The present studies evaluate the mechanism of action of two novel antifibrotic compounds, HOE 077 and Safironil, which were designed as competitive inhibitors of collagen protein synthesis. Fibrosis was induced in rats by administration of carbon tetrachloride, and activation was monitored as the level of collagen I mRNA or smooth muscle alpha-actin. Both male and female rats were studied. Stellate cell activation, rather than collagen synthesis, proved to be the target of both HOE 077 and Safironil in the intact liver. In culture, the drugs not only prevented the activation of stellate cells but also accelerated their deactivation. They were no more effective in co-cultures containing hepatocytes than in pure stellate cell cultures, indicating that metabolic conversion of HOE 077 was not required. Interestingly, the response of cells from females was greater than that of male cells, leading to the conclusion that stellate activation is sexually dimorphic. This finding may be relevant to the observation that fibrosis in chronic viral hepatitis progresses less rapidly and that hepatocellular carcinoma is less frequent in females than in males.