Inhibition of intrahepatic bile duct dilation of the polycystic kidney rat with a novel tyrosine kinase inhibitor gefitinib
Inhibition of intrahepatic bile duct dilation of the polycystic kidney rat with a novel tyrosine kinase inhibitor gefitinib
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DOI：
10.2353/ajpath.2006.051136
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发表时间：
2006-10-01
影响因子：
6
通讯作者：
Nakanuma, Yasuni
中科院分区：
文献类型：
--
作者：
Sato, Yasunori;Harada, Kenichi;Nakanuma, Yasuni
多囊肾（PCK）大鼠代表了对应于Caroli病伴先天性肝纤维化和常染色体隐性多囊肾病的肝和肾囊肿病理学。我们以前报道，表皮生长因子受体酪氨酸激酶抑制剂，吉非替尼（易瑞沙），显着抑制胆管上皮细胞的PCK大鼠在体外的异常生长。本研究探讨了吉非替尼在体内外对PCK大鼠囊肿发病的影响。胆管上皮细胞在胶原凝胶基质中的三维培养模型用于体外分析。对于体内实验，在3至10周龄之间用吉非替尼处理PCK和对照大鼠。在体外，吉非替尼对PCK大鼠胆管囊肿形成有较强的抑制作用。在体内，吉非替尼治疗显著抑制PCK大鼠肝内胆管的囊性扩张，同时伴有肝纤维化的改善。相比之下，由于治疗，没有观察到对肾囊肿发展的有益影响。这些结果表明，表皮生长因子受体介导的信号通路参与了胆管发育不全的PCK大鼠，囊肿进展的机制是不同的肝脏和肾脏之间。
The polycystic kidney (PCK) rat represents a liver and kidney cyst pathology corresponding to Caroli's disease with congenital hepatic fibrosis and autosomal recessive polycystic kidney disease. We previously reported that an epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), significantly inhibited the abnormal growth of biliary epithelial cells of PCK rats in vitro. This study investigated the effects of gefitinib on cyst pathogenesis of the PCK rat both in vitro and in vivo. A three-dimensional culture model of biliary epithelial cells in the collagen gel matrix was used for in vitro analysis. For in vivo experiments, PCK and control rats were treated with gefitinib between 3 and 10 weeks of age. In vitro, gefitinib had strong inhibitory effects on biliary cyst formation of PCK rats. In vivo, treatment with gefitinib significantly inhibited the cystic dilatation of the intrahepatic bile ducts of PCK rats, which was accompanied by improvement of liver fibrosis. By contrast, no beneficial effects were observed on renal cyst development because of the treatment. These results suggest that signaling pathways mediated by epidermal growth factor receptor are involved in biliary dysgenesis of the PCK rat, with the mechanisms of cyst progression being different between the liver and kidney.