Gliotoxin non-selectively induces apoptosis in fibrotic and normal livers
Gliotoxin non-selectively induces apoptosis in fibrotic and normal livers
复制标题
DOI：
10.1111/j.1478-3231.2005.01212.x
复制
发表时间：
2006-03-01
影响因子：
6.7
通讯作者：
Poelstra, K
中科院分区：
文献类型：
--
作者：
Hagens, WI;Olinga, P;Poelstra, K
背景：肝纤维化是慢性肝损伤的常见反应，最终导致肝硬化。有证据表明，诱导肝星状细胞（HSC）凋亡可能导致肝纤维化的消退。近年来研究表明，胶毒素（GTX）可诱导HSC凋亡。然而，由于缺乏细胞和组织特异性，GTX的临床使用可能受到限制，导致潜在严重不良反应的高风险。因此，本研究的目的是研究GTX对肝脏不同细胞的影响。方法：我们使用正常和纤维化大鼠肝切片，研究GTX对各种驻留肝细胞类型的影响。在这些切片中，复杂的细胞-细胞相互作用被保留，这非常接近于模拟体内情况。结果：GTX在上述脑片中表现出较强的促凋亡活性。免疫组化染色和实时mRNA技术均显示，在HSC中观察到这种凋亡诱导效应。然而，枯否细胞和肝脏内皮细胞也受到GTX的影响，而肝细胞仅受到轻度影响。结论：这项研究表明，诱导细胞凋亡策略治疗肝纤维化具有很大的潜力，但有必要开发一种针对HSC的特异性疗法来防止不良反应。
Background: Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis. Several lines of evidence indicate that inducing apoptosis of hepatic stellate cells (HSC) may lead to regression of liver fibrosis. Recently, it was shown that gliotoxin (GTX) induces apoptosis of HSC. However, the clinical use of GTX may be limited because of the lack of cell and tissue specificity, causing a high risk of potentially severe adverse effects. The aim of this study, therefore, was to study the effect of GTX on different cells of the liver. Methods: We used normal and fibrotic precision-cut rat liver slices to study the effect of GTX on the various resident liver cell types. In these slices, the complex cell-cell interactions are preserved, which closely mimics the in vivo situation. Results: GTX exhibited a potent apoptosis-inducing activity in these slices. Both immunohistochemical stainings and real-time mRNA techniques showed that this apoptosis-inducing effect was seen in HSC. However, Kupffer cells and liver endothelial cells were also affected by GTX, whereas hepatocytes were only mildly affected. Conclusions: This study indicates that the apoptosis-inducing strategy to treat liver fibrosis has high potential, but it will be necessary to develop an HSC-specific therapy to prevent adverse effects.