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

胆管消失综合征胆管上皮细胞再生受损的分子机制。

• 批准号: 15590297
• 负责人: SASAKI Motoko
• 金额: $ 2.3万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590297/
• 关键词: bile duct vanishing syndrome; primary biliary cirrhosis; trefoil factor family (TFF); intrahepatic bile duct; biliary epithelial cell; immunohistochemistry; cellular senescence; trefoil factor family(TFF); 原発性硬化性胆管炎; deleted in malignant brain tu

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.

胆管粘膜再生障碍可能与胆管消失综合征胆管缺损的发生有关。我们采用免疫组化方法检测了45例原发性胆汁性肝硬化（PBC）患者和65例正常对照肝组织中三叶因子家族（TFF）-1，2，3（TFF 2：DMBT 1的假定受体）、肝细胞生长因子（HGF）相关因子（HGFA、HAI-1、cMET）的表达以及肝内胆管细胞衰老的情况。在肝内胆管系统中，TFF 1 -3呈部位性分布，TFF 1、3和TFF 2分别在肝内大胆管和小胆管的黏膜修复中发挥作用。TFF 2、DMBT 1和HAI-1在PBC损伤胆管中表达增加。此外，PBC损伤胆管和慢性排斥肝组织中的胆管上皮细胞具有细胞衰老的特征，如p16^<INK4a>和p21^&lt;WAF 1/Cip&gt;表达增加。p16抑制子bmi 1表达减少<INK4a>参与了胆管上皮细胞的衰老过程。这些因子的mRNA表达与免疫组化检测的蛋白表达雅阁。氧化应激和几种细胞因子如TNF-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，氧化应激降低了bmi 1的表达，增加了p16^<INK4a>和p21^&lt;WAF 1/Cip&gt;的表达，并诱导了培养的小鼠胆管上皮细胞的细胞衰老。TFF-1、2、3和HGF相关因子共同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胆管再生障碍和继发性胆管缺损的主要原因。

项目成果

Expression profiles of MUC mucin core protein in the intrahepatic biliary system : Physiological distribution and pathological significance

肝内胆管系统MUC粘蛋白核心蛋白的表达谱：生理分布和病理意义

• 发表时间: 2005
• 期刊: Acta Histochemica et Cytochemica 38・5
• 作者: Motoko Sasaki;et al.
• 通讯作者: et al.

Frequent cellular senescence in small bile ducts in primary biliary cirrhosis: a possible role in bile duct loss

• DOI: 10.1002/path.1729
• 发表时间: 2005-03-01
• 期刊: JOURNAL OF PATHOLOGY
• 影响因子: 7.3
• 作者: Sasaki, M;Ikeda, H;Nakanuma, Y
• 通讯作者: Nakanuma, Y

Are bile duct lesions of primary biliary cirrhosis distinguishable from those of autoimmune hepatitis and chronic viral hepatitis? Interobserver histological agreement on trimmed bile ducts

原发性胆汁性肝硬化的胆管病变与自身免疫性肝炎和慢性病毒性肝炎的胆管病变有区别吗？

• 发表时间: 2005
• 期刊: Journal of Gastroenterology 40・2
• 作者: Zen Y;et al.
• 通讯作者: et al.

Decreased expression of bmil is closely associated with cellular senescence in small bite ducts in primary biliary cirrhosis.

bmil 表达减少与原发性胆汁性肝硬化小咬管细胞衰老密切相关。

• 发表时间: 2006
• 期刊: American Journal of Pathology (in press)
• 作者: Sasaki M;et al.
• 通讯作者: et al.

Expression of trefoil factor family-1, 2, and 3 is augmented in hepatolithiasis

肝结石中三叶因子家族 1、2 和 3 的表达增强

• 发表时间: 2004
• 期刊: Peptides 25・5
• 作者: Motoko Sasaki;et al.
• 通讯作者: et al.