Role of Mechanosensitive Receptors During Biliary Proliferation and Fibrosis

描述(由申请人提供)： 在慢性淤胆性肝病如原发性胆汁性肝硬变(PBC)和原发性硬化性胆管炎(PSC)的发病过程中，胆管细胞的生长和重塑对维持胆管质量和分泌功能至关重要。胆管细胞是胆道系统的衬里上皮细胞，参与多种细胞过程。在胆汁淤积性疾病中，胆管细胞通过其细胞活化产物被认为是胆管损伤和以慢性肝胆损伤为特征的上皮下纤维化之间的关键环节。针对组织损伤引起的机械应力做出反应的特定因子可能有助于限制在肝胆损伤和疾病(如PBC、PSC和肝纤维化)中发生的炎症和纤维化。新的证据表明，暴露在香烟烟雾中可能会刺激慢性肝病向纤维化的发展，如PSC、PBC、慢性丙型肝炎和非酒精性脂肪性肝病。尽管机械应激如胆管扩张(在PSC中常见)和烟草使用(在PBC患者中加速纤维化)会激活胆管细胞，但导致这种表型的细胞和分子机制尚不清楚。7-烟碱型乙酰胆碱受体(7-nAChR)介导尼古丁的增殖和致纤维化作用，也可被机械应激激活。我们提出的总体假设是，7-nAChR激活是介导促纤维化胆管细胞表型的关键和共同途径。这一假设将在三个特定的目标下进行测试，这将决定：(I)机械应激期间7-nAChR的配体依赖性激活是否通过增强miR-181和-200的表达而诱导促纤维化表型；(Ii)机械敏感的β7-nAChR的激活刺激钙依赖的ACh分泌和miR-181和-200的表达；以及(Iii)抑制7-nAChR是否可减轻胆汁淤积症BDL小鼠体内激活的胆汁表型和纤维化。拟议研究的完成将为理解机械刺激如何触发局部和全身反应介导肝胆纤维化提供一个框架。这一发现可能会导致胆汁淤积症的新治疗方法。 肝脏疾病和美国退伍军人肝病发病率和死亡率的降低。

DESCRIPTION (provided by applicant): Cholangiocyte growth and remodeling are critical for the maintenance of biliary mass and secretory function during the pathogenesis of chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Cholangiocytes, the epithelia lining the biliary system, participate in a diverse array of cellular processes. In cholestatic livr diseases, cholangiocytes, through the products of their cellular activation, are implicated as the key link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliary injury. Targeting specific factors that respond to the mechanical stress resulting from tissue injury may help limit inflammation and fibrosis that occur in hepatobiliary damages and diseases such as PBC, PSC and liver fibrosis. Emerging evidence indicates that exposure to cigarette smoke may stimulate the progression of chronic liver disease towards fibrosis such as PSC, PBC, chronic hepatitis C, and non-alcoholic fatty liver disease. Although mechanical stress such as occurs with biliary distention (commonly observed in PSC) and tobacco use (accelerates fibrosis in patients with PBC) activate cholangiocytes, the cellular and molecular mechanisms responsible for this phenotype remain unclear. The ¿7-nicotinic acetylcholine receptor (¿7-nAChR) mediates the proliferative and fibrogenic effects of nicotine and can also be activated by mechanical stress. We propose the overall hypothesis that ¿7-nAChR activation is a key and common pathway responsible for mediating the profibrogenic cholangiocyte phenotype. This postulate will be tested in three Specific Aims, which will determine whether (i) ligand-dependent activation of ¿7-nAChR during mechanical stress induces a profibrogenic phenotype via enhanced expression of miR-181 and -200; (ii) activation of mechanosensitive ¿7-nAChR stimulates Ca2+-dependent ACh secretion and miR-181 and -200 expression; and (iii) inhibition of ¿7-nAChR attenuates the activated biliary phenotype and fibrosis in vivo in cholestatic BDL mice. Completion of proposed studies will provide a framework for understanding how mechanical stimuli trigger local and systemic responses mediate hepatobiliary fibrosis. The findings will likely lead to new therapeutic approaches for cholestatic liver diseases and a reduction of morbidity and mortality in American Veterans with liver diseases.