Figure 2. A conceptual framework for the role of biliary oxysterols in biliary tract diseases.

Chronic or recurrent biliary tract infection, as represented by recurrent pyogenic cholangitis, bacterial colonization in gallstones and Opisthorchis viverrini infection, induces inflammation. This chronic inflammatory state is associated with activated leukocytes, which produce ROS mediated by NADPH oxidase and via the induction of proinflammatory cytokines such as IL-1 and IL-6. The resultant pro-oxidative milieu, represented by the relative overabundance of ROS/RNS induces the production of various oxysterol species through oxidation of biliary cholesterol. Biliary epithelial cells that are chronically exposed to these oxysterol species undergo apoptosis, DNA damage and repair, and altered mucin secretion. These physiologic effects are modulated by the bile acid milieu, perhaps through FXR- and TGR5-mediated mechanisms. Over time, a pathophysiologic response develops through failure of apoptosis and/or defective DNA repair, allowing a clone of resistant cells to undergo neoplastic change. Altered mucin secretion can also induce changes in the biliary milieu to favor gallstone formation.

ROS: Reactive oxygen species; RNS: Reactive nitrogen species.