title: Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China.
authors.forename: Qiu-Ming
authors.initials: QM
authors.lastname: Wang
authors.forename: Jian-Ling
authors.initials: JL
authors.lastname: Du
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Duan
authors.forename: Shi-Bin
authors.initials: SB
authors.lastname: Guo
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Sun
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002263:Carboxyhemoglobin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D064451:Hepcidins / Q000097:blood; D007501:Iron / Q000097:blood*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017082:Portal Pressure / Q000187:drug effects; D011524:Protoporphyrins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D064451:Hepcidins; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D011524:Protoporphyrins; D012333:RNA, Messenger; C576839:TIMP1 protein, rat; C508962:Tgfb1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D002245:Carbon Dioxide; C017803:zinc protoporphyrin; D008315:Malondialdehyde; C007095:cobaltiprotoporphyrin; D002263:Carboxyhemoglobin; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D013482:Superoxide Dismutase; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat
keywords: Bile duct ligation; Carboxyhemoglobin; Heme oxygenase-1; Hepcidin; Iron accumulation; Oxidative stress; Portal vein pressure