Basic Research
Copyright ©2007 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2007; 13(25): 3478-3486
Published online Jul 7, 2007. doi: 10.3748/wjg.v13.i25.3478
Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats
Matthias Froh, Lars Conzelmann, Peter Walbrun, Susanne Netter, Reiner Wiest, Michael D Wheeler, Mark Lehnert, Takehiko Uesugi, Jurgen Scholmerich, Ronald G Thurman
Matthias Froh, Peter Walbrun, Susanne Netter, Reiner Wiest, Jurgen Scholmerich, Department of Internal Medicine, University of Regensburg, Germany
Matthias Froh, Lars Conzelmann, Michael D Wheeler, Mark Lehnert, Takehiko Uesugi, Ronald G Thurman, Department of Pharmacology, University of North Carolina, United States
Lars Conzelmann, Department of Urology, University of Mainz, Germany
Mark Lehnert, Department of Surgery, University of Frankfurt, Germany
Takehiko Uesugi, Department of Surgery, University of Osaka, Japan
Author contributions: All authors contributed equally to the work.
Supported by grants from the National Institute of Health and by a grant from the Deutsche Forschungsgemeinschaft, No. FR 1644/4-1
Correspondence to: Matthias Froh, MD, Department of Internal Medicine, University of Regensburg, Regensburg 93042, Germany. matthias.froh@klinik.uni-regensburg.de
Telephone: +49-941-9447012 Fax: +49-941-9447011
Received: February 9, 2007
Revised: February 10, 2007
Accepted: March 31, 2007
Published online: July 7, 2007
Abstract

AIM: To investigate the effects of heme oxygenase-1 (HO-1) against oxidant-induced injury caused by bile duct ligation (BDL).

METHODS: Either cobalt protoporphyrin (CoPP), a HO-1 inducer, or saline were injected intraperitoneally in male SD-rats. Three days later, BDL or sham-operations were performed. Rats were sacrificed 3 wk after BDL and livers were harvested for histology. Fibrosis was evaluated by sirius red staining and image analysis. Alpha-smooth muscular actin, which indicates activation of stellate cells, was detected by immunohistochemical staining, and cytokine and collagen-Iα (Col-Iα) mRNA expression was detected using RNase protection assays.

RESULTS: Serum alanine transaminase increased 8-fold above normal levels one day after BDL. Surprisingly, enzyme release was not reduced in rats receiving CoPP. Liver fibrosis was evaluated 3 wk after BDL and the sirius red-positive area was found to be increased to about 7.8%. However, in CoPP pretreated rats sirius red-positive areas were increased to about 11.7% after BDL. Collagen-Iα and TGF-β mRNA increased significantly by BDL. Again, this effect was increased by HO-1 overexpression.

CONCLUSION: Hepatic fibrosis due to BDL is not reduced by the HO-1 inducer CoPP. In contrast, HO-1 overexpression increases liver injury in rats under conditions of experimental chronic cholestasis.

Keywords: Heme oxygenase-1; Bile duct ligation; Chronic cholestasis; Liver fibrosis; Serum alanine transaminase; Transforming growth factor-β; Tumor necrosis factor-Iα; TypeIcollagen