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

先天性肝纤维化与卡罗利氏病的病理和生物学分析——该病动物模型的比较研究

基本信息

批准号：
12470044
负责人：
NAKANUMA Yasuni
金额：
$ 2.24万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

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.

先天性肝纤维化（CHF）和先天性肝纤维化（HPVF）属于肝纤维多囊性病变。在这项研究中，我们使用了一种新的多囊肾（PCK）大鼠，它自发地发展肝囊肿，并描述了肝胆病变。1）PCK大鼠肝脏的囊性变化被发现是多个节段性和囊状的肝内胆管树的扩张。这些特征与Caroli病和CHF的特征非常相似，表明PCK大鼠可能是Caroli病合并CHF的有希望的动物模型。2）在PCK大鼠扩张的肝内胆管基底膜中，细胞外基质成分如层粘连蛋白和IV型胶原的表达减少或减弱，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CHF和Caroli病以及PCK大鼠的肝胆异常中起重要作用。3）CHF和Caroli病患者肝脏中CTGF和TGF-β等纤维化因子的表达模式与慢性肝炎和酒精性肝病患者不同，4）建立PCK大鼠肝内胆管上皮细胞（intraperitonealbiliaryepithelialcells，BECs）培养模型。PCK大鼠培养的BECs增殖活性高于对照组。cDNA微阵列分析显示与细胞增殖和凋亡相关的基因如MEK 5、TGF-β3和bFGF过表达。PCK大鼠BEC对EGF有高反应性，EGF受体酪氨酸激酶抑制剂可明显抑制PCK大鼠BEC的异常生长，为CHF和Caroli病的发病机制提供了新的认识。