血红素氧合酶-1调节大鼠免疫性肝纤维化形成的主要途径

AIM:Study regulation mechanisms of Hemeoxygenase-1(HO-1) in rat immune liver fibrosis to find routes for intervention in fibrosis.Material and Methods:Male Sprague-Dawley rats were divided randomly 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 F,Co and Zn, immune liver fibrosis was established with human serum albumin.At the attacked stage, CoPP(5mg/kg) and ZnPP(5mg/kg) were intraperitoneally injected in Co and Zn respectively. HO-1 in liver was detected by western blotting and immunohistochemistry. The indexs of fibrosis were assessed by radioimmunoassay. Concentrations of serum transforming growth factor-β1(TGF-β1), matrix metalloproteinases-1(MMP-1) and tissue inhibitor of metalloproteinses(TIMP-1) were detected using enzyme-linked immunosorbent assay(ELISA). Hepatic stellate cell(HSC) and proliferation degree of fibrosis were assessed by pathological examination. Results:The expression of HO-1 in F was significantly higher than in N,more increase in Co(P<0.05). In Zn,it was lower than in F (P<0.05),but still higher than in N (P<0.01).Compared with N,liver functional and liver fibrosis indicators were increased in F (P<0.01),while comparing to F ,they were decreased in Co (P<0.05) and increased in Zn (P<0.05).CoPP reduced the extent of hepatocellular injury and hepatic fibrosis in comparison with F (P<0.01),oppositing to the effect of ZnPP(P<0.01).HSC was observed using indirect method and the result showed that the number of HSC in F increased more than that in N and in Co，while much less than in Zn.The concentration of TGF-β1 decreased(Co,3.5±1.0,F,7.8±1.3ng/ml)when HO-1 expressed increasingly(P<0.01)and enhanced(Zn,9.6±13.6ng/ml) when HO-1 presented less(P<0.01). MMP-1/TIMP-1 ratio reduced in F(0.0323±0.008) compared to N(0.0935±0.004) (P<0.01).It increased obviously in Co(0.110±0.005) (P<0.01), and decreased in Zn(0.020±0.001)(P<0.01) compared to F. The infiltration of T lymphocytes cells in portal areas were much lower in Co than in F,while in Zn were more increased.Conclusion: Inducing HO-1 expression may lighten liver fibrosis, in contrast,inhibiting it strengthens the lesion. HO-1 interferes with the main ways to form liver fibrosis.

Heme oxygenase-1 regulates the major route involved in formation of immune hepatic fibrosis in rat