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

胆管消失综合征中胆管丧失的发病机制可能与胆道粘膜再生受损有关。我们检测了三叶因子家族(TFF)-1,2,3， TFF2的推定受体：DMBT1，肝细胞生长因子（HGF）相关因子（HGFA, hae -1,cMET）的表达以及肝内胆管细胞衰老的参与，这些患者来自胆管消失综合征患者（n=45），包括原发性胆汁性肝硬化（PBC）和对照肝脏（n=65）。在肝内胆道系统中，观察到TFF1-3的部位特征性分布，TFF1、3和TFF2分别参与肝内大胆管和小胆管的粘膜修复。PBC损伤胆管中TFF2、DMBT1、HAI-1表达升高。此外，胆道上皮细胞表现出细胞衰老特征，如PBC损伤胆管和慢性同种异体排斥肝脏中p16^<INK4a>和p21^<WAF1/Cip>的表达增加。bmi1 （p16^<INK4a>的抑制因子）的表达降低参与了胆道上皮细胞的衰老。这些因子的mRNA表达与免疫组化检测的蛋白表达一致。氧化应激和tnf - α等多种细胞因子增加了培养小鼠胆道上皮细胞中TFFs和HAI-1的表达。此外，氧化应激降低了bmi1的表达，增加了p16^<INK4a>和p21^<WAF1/Cip>的表达，诱导培养小鼠胆道上皮细胞衰老。综上所述，TFF-1、2、3和HGF相关因子参与了肝内胆道系统和胃肠道的粘膜修复系统。胆道上皮细胞的衰老可能是胆管消失综合征中胆管再生受损和胆管损失的主要原因。

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.