Control of Cholangiocyte Adaptive Responses by Visceral Hormones and Neuropeptides

Abstract

Cholangiocytes, the epithelial cells lining the biliary tree, are the target cells in several liver diseases, termed cholangiopathies. Cholangiopathies are a challenge for clinicians and an enigma for scientists, as the pathogenetic mechanisms by which they develop, and the therapeutic tools for these diseases are still undefined. Several studies demonstrate that many visceral hormones, neuropeptides, and neurotransmitters modulate the adaptive changes of cholangiocytes to chronic cholestatic injury. The aim of this review is to present the recent findings that contributed to clarify the role of visceral hormones and neuropeptides in the regulation of the pathophysiology of cholestasis. These studies helped to shed light on some aspects of cholangiocyte pathophysiology, revealing novel perspectives for the clinical managements of cholangiopathies.

Physiology of Cholangiocytes

“…Similarly, in isolated bivascularly perfused rat liver, arterial infusion of ACh accentuates secretin-stimulated HCO 3 − secretion (118). A decrease of secretin-stimulated bile flow and HCO 3 − secretion, was observed in cholangiocytes isolated from the liver of bile duct-ligated rats with total vagotomy; this further supports the role of parasympathetic innervation and its neurotransmitter, ACh, in the potentiation of secretin-stimulated HCO 3 − secretion (165,178,180,181).…”

“…ACh and adrenergic agonists do not influence basal cholangiocyte secretion of HCO 3 − de novo, but they significantly potentiate cholangiocyte HCO 3 − secretion that has been stimulated by secretin (164,178). These are described below.…”

Physiology of Cholangiocytes

“…Similarly, in isolated bivascularly perfused rat liver, arterial infusion of ACh accentuates secretin-stimulated HCO 3 − secretion (118). A decrease of secretin-stimulated bile flow and HCO 3 − secretion, was observed in cholangiocytes isolated from the liver of bile duct-ligated rats with total vagotomy; this further supports the role of parasympathetic innervation and its neurotransmitter, ACh, in the potentiation of secretin-stimulated HCO 3 − secretion (165,178,180,181).…”

“…ACh and adrenergic agonists do not influence basal cholangiocyte secretion of HCO 3 − de novo, but they significantly potentiate cholangiocyte HCO 3 − secretion that has been stimulated by secretin (164,178). These are described below.…”

Involvement of cholangiocyte proliferation in biliary fibrosis

“…In large cholangiocytes, secretin increases cyclic adenosine 3', 5'-monophosphate (cAMP) levels [4,[16][17][18][19] and induces the opening of the Clchannel (cystic fibrosis transmembrane conductance regulator, CFTR), which leads to the activation of the Cl-/HCO3-anion exchanger 2 (AE2) and the secretion of bicarbonate in bile [3] . In addition to their normal biliary function, cholangiocytes have also been found to detoxify xenobiotics [9][10][11][12] and they also provide one of the first lines of defense against microbes in the biliary system [7,20] . Our knowledge of the factors that control cholangiocyte function has greatly increased in recent years, due to an increased interest in liver diseases, such as biliary cancer, biliary fibrosis and cholestatic liver disease [7,[9][10][11].…”