| 20203062 |
von Montfort C, Beier JI, Kaiser JP, Guo L, Joshi-Barve S, Pritchard MT, States JC, Arteel GE: PAI-1 plays a protective role in CCl4-induced hepatic fibrosis in mice: role of hepatocyte division. Am J Physiol Gastrointest Liver Physiol. 2010 Mar 4.
Background & Aims: Plasminogen activator inhibitor-1 (PAI-1) is an acute phase protein that has been shown to play a role in experimental fibrosis caused by bile duct ligation (BDL) in mice. However, its role in more severe models of hepatic fibrosis (e.g., carbon tetrachloride; CCl (4)) has not been determined and is important for extrapolation to human disease. Methods: Wild-type or PAI-1 knockout mice were administered CCl (4) (1 ml/kg BW i.p.) 2x/wk for 4 wks. Plasma (e.g., transaminase activity) and histologic (e.g., Sirius red staining) indices of liver damage and fibrosis were evaluated. Proliferation and apoptosis were assessed by PCNA and TUNEL staining, respectively, as well as by indices of cell cycle (e.g., p53, cyclin D1). Results: In contrast to previous studies with BDL, hepatic fibrosis was enhanced in PAI-1 (-/-) mice after chronic CCl (4) administration. Indeed, all indices of liver damage were elevated in PAI-1 (-/-) mice compared to wild-type mice. This enhanced liver damage correlated with impaired hepatocyte proliferation. A similar effect on proliferation was observed after 1 bolus dose of CCl (4), without concomitant increases in liver damage. Under these conditions, a decrease in phospho-p38, coupled with elevated p53 protein, was observed; these results suggest impaired proliferation and a potential G (1)/S cell cycle arrest in PAI-1 (-/-) mice. Conclusion: These data suggest that PAI-1 may play multiple roles in chronic liver diseases, both protective and damaging, the latter mediated by its influence on inflammation and fibrosis, and the former via helping maintain hepatocyte division after an injury. |
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