The molecular mechanism of the impaired regeneration of biliary epithelial cells in bile duct vanishing syndrome.

胆管黏膜再生障碍可能与消失型胆管综合征胆管丢失的发病机制有关。应用免疫组织化学方法检测45例消失型胆管综合征(PBC)患者和65例对照肝组织中三叶因子家族(TFF)-1、2、3、TFF2受体DMBT1、肝细胞生长因子(HGF)相关因子(HGFA、HAI-1、cMET)的表达及肝内胆管细胞衰老的参与情况。在肝内胆管系统中，TFF1-3的分布具有部位特征，TFF1、TFF3和TFF2分别在大、小胆管的粘膜修复中起作用。PBC损伤胆管中TFF2、DMBT1和HAI-1的表达增加。此外，胆管上皮细胞具有细胞衰老的特征，如p16^&lt；INK4a&gt；和p21^&lt；WAF1/Cip&gt；在PBC受损的胆管和慢性排斥反应的肝脏中表达增加。P16^-lt；INK4a&gt抑制因子BMI1的表达降低参与了胆管上皮细胞的衰老。这些因子的mRNA表达与免疫组织化学检测到的蛋白表达一致。氧化应激和几种细胞因子如肿瘤坏死因子-α增加了培养的小鼠胆管上皮细胞中TFFs和HAI-1的表达。此外，氧化应激可降低小鼠胆管上皮细胞BMI1的表达，上调p16^&lt；INK4a&gt；和p21^&lt；WAF1/Cip&gt的表达，并诱导细胞衰老。总之，TFF-1、2、3和HGF相关因子参与了肝内胆管系统和胃肠道的粘膜修复系统。胆管上皮细胞的衰老可能是胆管消失综合征患者再生功能受损和继发胆管丢失的主要原因。

The impaired regeneration of biliary mucosa may be related to the pathogenesis of bile duct loss in vanishing bile duct syndrome. We examined immunohistochemically the expression of trefoil factor family (TFF)-1,2,3, a putative receptor for TFF2:DMBT1, hepatocytes growth factor (HGF) related factors (HGFA,HAI-1,cMET) and the involvement of cellular senescence in intrahepatic bile ducts in the livers taken form the patients with vanishing bile duct syndrome (n=45) including primary biliary cirrhosis (PBC) and control livers (n=65). In intrahepatic biliary system, the site-characteristic distribution of TFF1-3 was seen and TFF1, 3 and TFF2 play a role in the mucosal repair in large and small intrahepatic bile ducts, respectively. The expression of TFF2, DMBT1 and HAI-1 was increased in the damaged bile ducts in PBC. Furthermore, the biliary epithelial cells showed the features for cellular senescence such as the increased expression of p16^<INK4a> and p21^<WAF1/Cip> in the damaged bile ducts in PBC and in the livers of chronic allograft rejection. The decreased expression of bmi1, a represser of p16^<INK4a> was involved in the cellular senescence of biliary epithelial cells. The mRNA expression of these factors was in accord with the protein expression detected by immunohistochemistry. The oxidative stress and several cytokines such as TNF-alpha increased the expression of TFFs and HAI-1 in cultured mouse biliary epithelial cells. In addition, oxidative stress decreased the expression of bmi1, increased the expression of p16^<INK4a> and p21^<WAF1/Cip> and induced cellular senescence in cultured mouse biliary epithelial cells. Taken together, TFF-1,2,3 and HGF related factors were involved in the mucosal repair system in the intrahepatic biliary system as well as in the gastrointestinal tracts. The cellular senescence of biliary epithelial cells may be a main cause for the impaired regeneration and following bile duct loss in vanishing bile duct syndrome.