Fibrosis of the liver in rats induced by bile duct ligation: Effects of inhibition of prolyl 4-hydroxylase

The model of biliary cirrhosis by bile duct ligation was further characterized using PIIIP, 7S-collagen as well as standard enzymes in the serum, prolyl 4-hydroxylase and total hydroxyproline in the liver and light microscopical histology. Five weeks after bile duct ligation there was an increase in total collagen content of the liver to 510% of initial values accompanied by an increase of serum-PIIIP (225%) and 7S-collagen (389%). The time-course of this connective tissue proliferation was biphasic with an initial phase of cholestasis and cellular damage followed by rapidly increasing collagen accumulation. The novel prolyl 4-hydroxylase inhibitor HOE 077 reduced the accumulation of collagen in the liver over 6 weeks by 48%. There were no apparent side effects and treated animals showed a tendency towards less functional impairment. The drug's effects, however, were not dose-dependent between daily doses of two times 2 mg/kg and two times 10 mg/kg. These results emphasize the usefulness of the bile duct ligation model for studies of collagen metabolism. They show HOE 077 to be a promising agent for the inhibition of hepatic fibrosis.