title: Heme oxygenase-1 regulates the major route involved in formation of immune hepatic fibrosis in rats.
abstract: BACKGROUND
  Heme oxygenase (HO) plays roles in some liver diseases, but what it does in immune liver fibrosis is rarely reported. We investigated the regulation mechanisms of HO-1 in rat immune liver fibrosis to find routes for intervention.
  
  
  METHODS
  Male Sprague-Dawley rats were randomly divided into control group (N, n = 12), fibrosis group (F, n = 20), cobalt protoporphyrin (CoPP) inducing group (Co, n = 20) and zinc protoporphyrin (ZnPP) inhibiting group (Zn, n = 20). In groups F, Co and Zn, immune liver fibrosis was established with human serum albumin. At the attacked stage, CoPP (5 mg/kg) and ZnPP (5 mg/kg) were intraperitoneally injected in groups Co and Zn, respectively. After establishment of rat models, the numbers of rats reduced to 11, 15, 17 and 12 in groups N, F, Co and Zn respectively, because of death during the process. HO-1 in liver was detected by Western blotting and immunohistochemistry. The indexes of fibrosis were assessed by radioimmunoassay. Concentrations of serum transforming growth factor-β1 (TGF-β1), and tissue inhibitor of metalloproteinses (TIMP-1) were detected using enzyme-linked immunosorbent assay. Hepatic stellate cell (HSC) and proliferation degree of fibrosis were assessed by pathological examination. Data analysis was performed by SPSS 10.0 software.
  
  
  RESULTS
  The expression of HO-1 in group F was significantly higher than that in group N, but lower than that in group Co (P < 0.05); while that in group Zn was lower than in group F (P < 0.05), but still higher than that in group N (P < 0.01). Compared with group N, liver functional and liver fibrosis indicators were increased in group F (P < 0.01), while comparing to group F, they were decreased in group Co (P < 0.05) and increased in group Zn (P < 0.05). CoPP reduced the extent of hepatocellular injury and hepatic fibrosis in comparison with group F (P < 0.01), being the opposite effect of ZnPP (P < 0.01). HSC was observed using indirect method and the result showed that the number of HSC in group F increased more than that in groups N and Co, while much less than in group Zn. The concentration of TGF-β1 decreased when HO-1 expressed increasingly (group Co: (3.5 ± 1.0) ng/ml, group F: (7.8 ± 1.3) ng/ml, P < 0.01) and enhanced (group Zn: (9.6 ± 13.6) ng/ml) when HO-1 presented less (P < 0.01). The concentrations of TIMP-1 were (151.1 ± 32.0), (472.0 ± 34.8), (232.3 ± 41.3) and (533.2 ± 37.2) ng/g liver wet weight in groups N, F, Co, and Zn, respectively. It was reduced in group Co (P < 0.01) and increased in group Zn compared with group F (P < 0.05).
  
  
  CONCLUSIONS
  Inducing HO-1 expression appropriately may lighten hepatic fibrosis, and in contrast, inhibiting it strengthens the lesion. HO-1 interferes with the main ways to form liver fibrosis.
authors.affiliation: Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China. cathydoctor@sina.com
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Duan
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Sun
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Sun
authors.forename: Miao-Lei
authors.initials: ML
authors.lastname: Zheng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D051547:Heme Oxygenase-1