Bile duct ligation in rats induces biliary expression of cytokine-induced neutrophil chemoattractant

Background & Aims: Bile duct obstruction causes neutrophilic inflammation o f the liver and leads to hepatic fibrosis, In obstructive liver disease, th e localization of neutrophils in portal tracts suggests that cells within t his region produce neutrophil chemoattractants. In this study, we investiga ted whether bile duct obstruction in rats induces portal expression of cyto kine-induced neutrophil chemoattractant (CINC). Methods: Rats underwent bil e duct ligation for 3 hours to 8 days, CINC regulation was examined in vivo at various intervals by immunohistochemistry, ribonuclease protection, and in situ hybridization. CINC production was also investigated in cell cultu re, in response to putative stimuli from obstructed liver, Results: Bile du ct ligation caused neutrophilic infiltration of the liver within 3 hours. C INC was also rapidly induced, with specific expression identified in biliar y cells. Rat intrahepatic biliary cells produced CINC constitutively in cul ture; when exposed to cholestatic bile, they showed a 12-fold increase in C INC secretion, The effect of bile was not attributable to toxicity or to di ssolved cytokines or endotoxin. Mechanical strain, designed to mimic the st retching of biliary cells during obstruction, did not induce CINC. Conclusi ons: Biliary cells contribute to hepatic inflammation during cholestasis by producing neutrophil chemoattractants. A major stimulus to biliary chemoat tractant production in vivo may be bile itself.