Neuroendocrine Regulation of Biliary Growth and Fibrosis
In cholestatic liver diseases, cholangiocytes, through the secretion of neuroendocrine factors, are the keylink 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 limitinflammation and liver fibrosis that occur in hepatobiliary damage and diseases such as primary biliarycirrhosis (PBC), primary sclerosing cholangitis (PSC) and liver fibrosis. Although mechanical stress occurswith biliary distention (commonly observed in PSC and extrahepatic cholestasis) and activatescholangiocytes, the cellular and molecular mechanisms responsible for this activated neuroendocrinephenotypes remain unclear. While advances have been made to further our understanding of the paracrineand autocrine neuroendocrine factors that modulate biliary proliferation during cholestasis, unfortunately,viable therapies for management of cholangiopathies remain elusive. There remains, therefore, a criticalneed 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 ofeffective therapeutic agents. Preliminary data from the analysis of the activated neuroendocrinecholangiocyte phenotypes demonstrated that: (i) cholangiocytes express serotonin receptors (5-HTR) (2A, 2Band 2C); (ii) mechanical stress-dependent activation of 5-HTR2B stimulates 5-HT synthesis and secretion andan 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 andsecretion of FGF1 (regulated by miR-16) stimulates biliary proliferation during in vitro mechanical stress andbile duct ligation (BDL). Based upon these findings, we propose the overall central hypothesis that themechanosensitive 5-HTÃ¨5-HTR2A/BCÃ¨FGF1 signaling axis is a key pathway responsible for mediating theproliferative 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 anactivated neuroendocrine and profibrogenic cholangiocyte phenotype mediated by activation of 5-HTR2A/B/Creceptor family; (ii) FGF1 secretion by cholangiocytes during cholestasis mediates biliary proliferation andthe 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/CÃ¨FGF1 axis attenuates theactivated neuroendocrine biliary phenotype and fibrosis during cholestasis. Completion of proposed studieswill provide a framework for understanding how mechanical stimuli trigger local and systemic responsesmediate hepatobiliary fibrosis.