Pathological and biological analysis of congenital hepatic fibrosis and Caroli's disease -A comparative study using an animal model for the disease

Carolis病和先天性肝纤维化(CHF)属于肝纤维多囊疾病。在这项研究中，我们使用了一种新的多囊肾(PCK)大鼠，它自发地形成肝囊肿，并对肝胆管病变进行了表征。1)PCK大鼠的肝脏囊性改变是肝内胆管树的多节段性和囊状扩张。这些特征与Caroli病和CHF非常相似，表明PCK大鼠有可能成为Caroli病合并CHF的动物模型。2)在PCK大鼠扩张的肝内胆管基底膜上，层粘连蛋白和IV型胶原等细胞外基质成分的表达减少或减少，在CHF和Caroli病患者的肝脏中也观察到同样的现象。胆管上皮细胞与周围基底膜的异常相互作用可能在慢性充血性心力衰竭、卡氏病大鼠及慢性酒精性肝病大鼠肝内胆管功能异常中起重要作用。3)慢性心力衰竭、卡氏病大鼠肝组织中结缔组织生长因子、转化生长因子-β的表达模式与慢性肝炎、酒精性肝病不同，提示这些疾病存在不同的肝纤维化机制。PCK大鼠培养的BECs增殖活性高于对照组。基因芯片分析显示与细胞增殖和凋亡相关的基因如MEK5、转化生长因子-β-3和碱性成纤维细胞生长因子过表达。PCK大鼠的BECs对EGF具有高反应性，EGF受体酪氨酸激酶抑制剂显著抑制了PCK大鼠BECs的异常生长，为CHF和Caroli病的发病机制提供了新的思路。

Carolis disease and congenital hepatic fibrosis(CHF) belong to hepatic fibropolycystic disease. In this study, we used a novel polycystic kidney(PCK) rat, which spontaneously develops hepatic cysts, and characterized the hepatobiliary lesions.1)The cystic changes of the liver of the PCK rats were found to be multiple segmental and saccular dilatations of the intrahepatic biliary tree. These features were very similar to those of Caroli's disease and CHF, demonstrating that the PCK rat could be a promising animal model of Caroli's disease with CHF.2)In the basement membrane of the dilated intrahepatic bile ducts of PCK rats, the expression of extracellular matrix components such as laminin and type IV collangen were reduced or diminished, and the same phenomena were observed In the liver of patients with CHF and Caroli's disease. Abnormal interactions between bile duct epithelia and surrounding basement membrane may play an important role in the hepatobiliary abnormalities of CHF and Caroli's disease as well as the PCK rats.3)The expression pattern of fibrogenic factors such as CTGF and TGF-β in the patient liver of CHF and Caroli's disease was different from those of the chronic hepatitis and alcoholic liver disease, suggesting that different mechanism of hepatic fibrosis exists in these disease.4)The cultured intrahepatic biliary epithelial cells(BECs) of the PCK rats were established. Proliferative activity of the cultured BECs of PCK rats were higher than those of the control rats. cDNA microarray analysis showed overexpression of the genes associated with cell proliferation and apoptosis such as MEK5, TGF-β3 and bFGF. The BECs of PCK rats were shown to be hyperresponsive to EGF, and EGF receptor tyrosine kinase inhibitor significantly inhibited abnormal growth of BECs of the PCK rats.The data obtained here provide insights into the pathogenesis of CHF and Caroli's disease.