Original Article
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. May 21, 2013; 19(19): 2921-2934
Published online May 21, 2013. doi: 10.3748/wjg.v19.i19.2921
Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation
Qiu-Ming Wang, Jian-Ling Du, Zhi-Jun Duan, Shi-Bin Guo, Xiao-Yu Sun, Zhen Liu
Qiu-Ming Wang, Zhi-Jun Duan, Shi-Bin Guo, Xiao-Yu Sun, Zhen Liu, Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
Jian-Ling Du, Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
Author contributions: Wang QM and Du JL performed the experiments, analyzed the data and wrote the manuscript; Duan ZJ and Wang QM designed the experiments; Wang QM performed the experiments, analyzed the data and wrote the manuscript; Duan ZJ and Guo SB revised the manuscript.
Supported by Grants from the National Natural Science Foundation of China, No. 30970886; The Science and Technology Project of Dalian, No. 2010E15SF179; and the Initial Doctoral funding of Liaoning Province, No. 20121110
Correspondence to: Zhi-Jun Duan, Professor, Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian 116011, Liaoning Province, China. cathydoctor@sina.com
Telephone: +86-411-83635963 Fax: +86-411-83632383
Received: January 13, 2013
Revised: March 15, 2013
Accepted: March 28, 2013
Published online: May 21, 2013
Abstract

AIM: To investigate the effects of the heme oxygenase (HO)-1/carbon monoxide system on iron deposition and portal pressure in rats with hepatic fibrosis induced by bile duct ligation (BDL).

METHODS: Male Sprague-Dawley rats were divided randomly into a Sham group, BDL group, Fe group, deferoxamine (DFX) group, zinc protoporphyrin (ZnPP) group and cobalt protoporphyrin (CoPP) group. The levels of HO-1 were detected using different methods. The serum carboxyhemoglobin (COHb), iron, and portal vein pressure (PVP) were also quantified. The plasma and mRNA levels of hepcidin were measured. Hepatic fibrosis and its main pathway were assessed using Van Gieson’s stain, hydroxyproline, transforming growth factor-β1 (TGF-β1), nuclear factor-E2-related factor 2 (Nrf2), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1).

RESULTS: Serum COHb and protein and mRNA expression levels of HO-1 and Nrf2 were increased in the BDL group compared with the Sham group and were much higher in the CoPP group. The ZnPP group showed lower expression of HO-1 and Nrf2 and lower COHb. The levels of iron and PVP were enhanced in the BDL group but were lower in the ZnPP and DFX groups and were higher in the CoPP and Fe groups. Hepcidin levels were higher, whereas superoxide dismutase levels were increased and malonaldehyde levels were decreased in the ZnPP and DFX groups. The ZnPP group also showed inhibited TGF-β1 expression and regulated TIMP-1/MMP-2 expression, as well as obviously attenuated liver fibrosis.

CONCLUSION: Reducing hepatic iron deposition and CO levels by inhibiting HO-1 activity though the Nrf2/Keap pathway could be helpful in improving hepatic fibrosis and regulating PVP.

Keywords: Heme oxygenase-1, Hepcidin, Iron accumulation, Oxidative stress, Portal vein pressure, Carboxyhemoglobin, Bile duct ligation

Core tip: In this study, inhibiting heme oxygenase-1 (HO-1)/carbon monoxide (CO) system by zinc protoporphyrin in rat liver fibrosis induced by bile duct ligation, the author aimed to affect the HO-1/CO system by iron deposition and portal pressure. Reducing hepatic iron deposition and CO levels by inhibiting HO-1 activity though the nuclear factor-E2-related factor 2/Keap pathway could be helpful in improving hepatic fibrosis and maintaining portal vein pressure.