Hagens Werner I, Olinga Peter, Meijer Dirk K F, Groothuis Geny M M, Beljaars Leonie, Poelstra Klaas
Department of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, Groningen, The Netherlands.
Liver Int. 2006 Mar;26(2):232-9. doi: 10.1111/j.1478-3231.2005.01212.x.
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.
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.
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.
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.
肝纤维化是慢性肝损伤的常见反应，最终会导致肝硬化。多项证据表明，诱导肝星状细胞（HSC）凋亡可能会使肝纤维化消退。最近有研究表明，胶质毒素（GTX）可诱导HSC凋亡。然而，由于缺乏细胞和组织特异性，GTX的临床应用可能受到限制，这会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。
我们使用正常和纤维化的大鼠肝脏精密切片来研究GTX对各种驻留肝细胞类型的影响。在这些切片中，复杂的细胞间相互作用得以保留，这与体内情况极为相似。
GTX在这些切片中表现出强大的诱导凋亡活性。免疫组织化学染色和实时mRNA技术均显示，这种诱导凋亡的作用在HSC中可见。然而，库普弗细胞和肝内皮细胞也受到GTX的影响，而肝细胞仅受到轻微影响。
本研究表明，诱导凋亡治疗肝纤维化的策略具有很大潜力，但有必要开发一种针对HSC的特异性疗法以预防不良反应。
