Central role for cholangiocyte pathobiology in cholestatic liver diseases.

Abstract

Cholangiopathies comprise a spectrum of chronic intra- and extrahepatic biliary tract disorders culminating in progressive cholestatic liver injury, fibrosis and often cirrhosis and its sequela. Treatment for these diseases is limited and collectively they are one of the therapeutic "black boxes" in clinical hepatology. The etiopathogenesis of the cholangiopathies likely includes disease-specific mediators, but also common cellular and molecular events driving disease progression (e.g., cholestatic fibrogenesis, inflammation, and duct damage). The common pathways involve cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, which are central to the pathogenesis of these disorders. Current information suggests that cholangiocytes function as a signaling "hub" in biliary tract-associated injury. Herein, we review the pivotal role of cholangiocytes in cholestatic fibrogenesis, focusing on crosstalk between cholangiocytes and portal fibroblasts and hepatic stellate cells. The proclivity of these cells to undergo a senescence-associated secretory phenotype which is pro-inflammatory and -fibrogenic, and the intrinsic intracellular activation pathways resulting in secretion of cytokines and chemokines is reviewed. The crosstalk between cholangiocytes and cells of the innate (neutrophils and macrophages), and adaptive (T-cells and B-cells) immune systems is also examined in detail. The information will help consolidate information on this topic, guide further research and potential therapeutic strategies for these diseases.