Biliary epithelial cell response to cholestasis

Abstract

T ENTIRE biliary tract is lined by a single layer of epithelial cells that, besides purely conveying functions, modify canalicular bile composition through vectorial transport of water, electrolytes and macromolecules. This transport activity depends upon the polarized distribution of plasma membrane proteins. Fluid ductular secretion represents 20 to 40% of total bile flow in humans, and is stimulated essentially by secretin and the vasoactive intestinal polypeptide. Secretin via a CAMP transient increase, stimulates the combined activities of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and of the anion exchanger (AE-2), both of which are located in the apical domain of biliary epithelial cells. Their activation results in water and bicarbonate secretion, leading to bile dilution and alkalinization. Biliary epithelial cells are also committed to absorption. The apical sodium-dependent bile acid transporter (ASBT) is present in the apical domain of biliary epithelial cells, where it may provide a cholehepatic shunt pathway for conjugated bile acids via the peribiliary vascular plexus (1). A general feature of cholestatic liver injury is the increase in bile ductular structures, referred to as “ductular reaction”. Depending on the type of injury, the ductular reaction may be “typical” and result from proliferation of pre-existing bile duct epithelial cells, or “atypical” and resplt from metaplasia of hepatocytes or from hepatic stem cell proliferation (2). The typical ductular reaction induced by acute biliary obstruction is associated with a marked increase in ductular secretion, and may therefore be regarded as an escape route for bile flow. Secretin-induced ductal secretion is exacerbated due to both an increase in the number of bile ducts and an up-regulation of secretin receptors (3). The cholehepatic shunt pathway may also be