A reversible model for periportal fibrosis and a refined alternative to bile duct ligation

Abstract

Bile duct ligation (BDL) is commonly employed as a model for hepatic periportal fibrosis. However, BDL is limited in that it is a severe procedure; is irreversible in practice; the severity of injury cannot be modulated and the procedure is associated with high mortality. Methapyrilene (MP) administration has therefore been investigated as an alternative model. Male rats were subjected to BDL or orally dosed with 150 mg MP per kg body weight 3 times per week for up to 6 weeks. Both procedures resulted in increases in serum alkaline phosphatase enzyme levels and periportal liver injury as judged by marked inflammatory cell recruitment to the periportal regions of the liver lobule. Injury in both models was associated with an accumulation of pro-fibrogenic myofibroblast and fibroblast populations – and to fibrosis – in the periportal regions of the liver lobule. Both procedures also caused an expansion in the number of biliary epithelial cells and a ductular reaction. However, the studies with MP resulted in no rat mortality, in contrast to the BDL procedure. Injury, inflammation, fibrosis and the ductular reaction that occurred in response to MP treatment all reversed within 3 weeks after MP treatment withdrawal. The MP model of periportal fibrosis is therefore a superior – more refined – model of periportal fibrosis than BDL since the degree of injury may be modulated (through alterations in injuring MP dose); the procedure is less severe; is subject to minimal mortality and is reversible (and therefore a more sensitive model to identify effective anti-fibrogenic drugs).