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

Background & Aims: Bile duct obstruction causes neutrophilic inflammation of the liver and leads to hepatic fibrosis, In obstructive liver disease, the localization of neutrophils in portal tracts suggests that cells within this region produce neutrophil chemoattractants. In this study, we investigated whether bile duct obstruction in rats induces portal expression of cytokine-induced neutrophil chemoattractant (CINC). Methods: Rats underwent bile 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 culture, in response to putative stimuli from obstructed liver, Results: Bile duct ligation caused neutrophilic infiltration of the liver within 3 hours. CINC was also rapidly induced, with specific expression identified in biliary cells. Rat intrahepatic biliary cells produced CINC constitutively in culture; when exposed to cholestatic bile, they showed a 12-fold increase in CINC secretion, The effect of bile was not attributable to toxicity or to dissolved cytokines or endotoxin. Mechanical strain, designed to mimic the stretching of biliary cells during obstruction, did not induce CINC. Conclusions: Biliary cells contribute to hepatic inflammation during cholestasis by producing neutrophil chemoattractants. A major stimulus to biliary chemoattractant production in vivo may be bile itself.