Neuroendocrine Regulation of Biliary Growth and Fibrosis

在胆汁淤积性肝病中，胆管细胞通过分泌神经内分泌因子，是关键 胆管损伤与慢性肝胆损伤的特征性上皮下纤维化之间的联系。 针对对组织损伤引起的机械应力作出反应的因素可以限制 炎症和肝纤维化发生在肝胆损伤和疾病，如原发性胆道 肝硬化（PBC）、原发性硬化性胆管炎（PSC）和肝纤维化。虽然机械应力会发生 伴有胆道扩张（通常在PSC和肝外胆汁淤积中观察到），并激活 胆管细胞，负责这种激活的神经内分泌的细胞和分子机制 表型仍不清楚。虽然我们对旁分泌的理解有了进一步的进展， 和自分泌神经内分泌因子调节胆汁淤积期间的胆汁增殖，不幸的是， 用于控制胆管病的可行疗法仍然难以捉摸。因此，仍然存在一个关键的 需要了解胆汁淤积期间胆管细胞生长的触发因素及其对损伤的反应， 这可能有助于确定代表发展的可行目标的关键信号通路， 有效的治疗剂。从激活的神经内分泌分析的初步数据 胆管细胞表型表明：（i）胆管细胞表达5-羟色胺受体（5-HTR）（2A，2B 和2C）;（ii）5-HTR 2B的机械应力依赖性激活刺激5-HT合成和分泌， PKA和miR-16介导机制中的活化的神经内分泌胆管细胞表型;（iii） 机械敏感性5-HTR 2B信号传导的激活与胆管细胞表达的增加一致， FGF 1的分泌（受miR-16调节）在体外机械应力期间刺激胆管增殖， 胆管结扎术（BDL）。基于这些发现，我们提出了总体中心假设，即 机械敏感性5-HTè 5-HTR 2A/BCèFGF 1信号轴是一个关键途径，负责介导 增殖和促纤维化胆管细胞表型。这一假设将在三个具体目标中得到检验， 这将证明：（i）机械应力依赖性5-HT合成和释放诱导了 5-HTR 2A/B/C激活介导的活化的神经内分泌和促纤维化胆管细胞表型 受体家族;（ii）胆汁淤积期间胆管细胞分泌FGF 1介导胆汁增殖， 5-HTR 2A/B/C受体家族中活化的神经内分泌胆管细胞表型和miR-16- 依赖性自分泌/旁分泌机制;和（iii）5-HTR 2A/B/CèFGF 1轴的抑制减弱 胆汁淤积时神经内分泌表型激活和纤维化。完成拟议的研究 将为理解机械刺激如何触发局部和系统反应提供一个框架 介导肝胆纤维化。

In cholestatic liver diseases, cholangiocytes, through the secretion of neuroendocrine factors, are the key link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliary injury. Targeting the factors that respond to the mechanical stress resulting from tissue injury may limit inflammation and liver fibrosis that occur in hepatobiliary damage and diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and liver fibrosis. Although mechanical stress occurs with biliary distention (commonly observed in PSC and extrahepatic cholestasis) and activates cholangiocytes, the cellular and molecular mechanisms responsible for this activated neuroendocrine phenotypes remain unclear. While advances have been made to further our understanding of the paracrine and autocrine neuroendocrine factors that modulate biliary proliferation during cholestasis, unfortunately, viable therapies for management of cholangiopathies remain elusive. There remains, therefore, a critical need to understand the triggers of cholangiocyte growth and their responses to damage during cholestasis, which may help identify key signaling pathways that represent viable targets for the development of effective therapeutic agents. Preliminary data from the analysis of the activated neuroendocrine cholangiocyte phenotypes demonstrated that: (i) cholangiocytes express serotonin receptors (5-HTR) (2A, 2B and 2C); (ii) mechanical stress-dependent activation of 5-HTR2B stimulates 5-HT synthesis and secretion and an activated neuroendocrine cholangiocyte phenotype in a PKA and miR-16 mediated mechanism; (iii) activation of mechanosensitive 5-HTR2B signaling in concert with increased cholangiocyte expression and secretion of FGF1 (regulated by miR-16) stimulates biliary proliferation during in vitro mechanical stress and bile duct ligation (BDL). Based upon these findings, we propose the overall central hypothesis that the mechanosensitive 5-HTè5-HTR2A/BCèFGF1 signaling axis is a key pathway responsible for mediating the proliferative and profibrogenic cholangiocyte phenotype. This postulate will be tested in three specific aims, which will demonstrate that: (i) mechanical stress-dependent 5-HT synthesis and release induces an activated neuroendocrine and profibrogenic cholangiocyte phenotype mediated by activation of 5-HTR2A/B/C receptor family; (ii) FGF1 secretion by cholangiocytes during cholestasis mediates biliary proliferation and the activated neuroendocrine cholangiocyte phenotype in a 5-HTR2A/B/C receptor family and miR-16- dependent autocrine/paracrine mechanism; and (iii) inhibition of the 5-HTR2A/B/CèFGF1 axis attenuates the activated neuroendocrine biliary phenotype and fibrosis during cholestasis. Completion of proposed studies will provide a framework for understanding how mechanical stimuli trigger local and systemic responses mediate hepatobiliary fibrosis.