Fibrosis of the liver in rats induced by bile duct ligation. Effects of inhibition by 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.
Böker
K
K
Department of Gastroenterology and Hepatology, Medizinische Hochschule, Hannover, Federal Republic of Germany.
Schwarting
G
G
Kaule
G
G
Günzler
V
V
Schmidt
E
E
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002802:Cholinesterases / Q000097:blood; D003094:Collagen / Q000097:blood / Q000378:metabolism; D006909:Hydroxyproline / Q000032:analysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D008111:Liver Function Tests; D008297:Male; D009929:Organ Size; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains
D015415:Biomarkers; D011725:Pyridines; C074630:lufironil; D003094:Collagen; D011393:Procollagen-Proline Dioxygenase; D002802:Cholinesterases; D006909:Hydroxyproline