Cholinergic system modulates growth, apoptosis, and secretion of cholangiocytes from bile duct-ligated rats

Background & Aims: To investigate the role of the cholinergic system in reg ulation of cholangiocyte functions, we evaluated the effects of vagotomy on cholangiocyte proliferation and secretion in rats that underwent bile duct ligation (BDL rats). Methods: After bile duct ligation (BDL), the vagus ne rve was resected; 7 days later, expression of M3 acetylcholine receptor was evaluated. Cholangiocyte proliferation was assessed by morphometry and mea surement of DNA synthesis. Apoptosis was evaluated by light microscopy and annexin-V staining. Ductal secretion was evaluated by measurement of secret in-induced choleresis, secretin receptor (SR) gene expression, and cyclic a denosine 3',5'-monophosphate (cAMP) levels. Results: Vagotomy decreased the expression of M3 acetylcholine receptors in cholangiocytes. DNA synthesis and ductal mass were markedly decreased, whereas cholangiocyte apoptosis wa s increased by vagotomy. Vagotomy decreased ductal secretion. Forskolin tre atment prevented the decrease in cAMP levels induced by vagotomy, maintaine d cholangiocyte proliferation, and decreased cholangiocyte apoptosis caused by vagotomy in BDL rats. Cholangiocyte secretion was also maintained by fo rskolin. Conclusions: Vagotomy impairs cholangiocyte proliferation and enha nces apoptosis, leading to decreased ductal mass in response to BDL. Secret in-induced choleresis of BDL rats was virtually eliminated by vagotomy in a ssociation with decreased cholangiocyte cAMP levels. Maintenance of cAMP le vels by forskolin administration prevents the effects of vagotomy on cholan giocyte proliferation, apoptosis, and secretion.