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Molecular Medicine

, Volume 23, Issue 1, pp 215–224 | Cite as

The Protective Effect of Heme Oxygenase-1 against Intestinal Barrier Dysfunction in Cholestatic Liver Injury Is Associated with NF-κB Inhibition

  • Lijing Zhang
  • Zhenling Zhang
  • Bojia Liu
  • Yanling Jin
  • Yan Tian
  • Yi Xin
  • Zhijun Duan
Research Article

Abstract

Heme oxygenase-1 (HO-1) is reported to protect against liver injury, but little Is known about its effect on the intestinal barrier in cholestatic liver injury. In this study, we investigated the effects of HO-1 and its enzymatic by-product on intestinal barrier dysfunction in bile duct ligation (BDL) rats and explored the possible mechanism. The HO-1 inducer cobalt protoporphyrin (CoPP) and carbon monoxide-releasing molecule-2 (CORM-2) were used; the expression levels of tight junction (TJ) proteins, intestinal inflammation and NF-κB p65 were measured. For an in vitro experiment, stable Caco-2 cell lines were constructed, one overexpressed the HO-1 gene and another with that gene knocked down, and the specific NF-κB inhibitor JSH-23 was used. CoPP and CORM-2 treatment alleviated liver and intestinal mucosa injury in BDL rats; improved ZO-1, claudin-1 and PCNA expression; and reduced cell apoptosis and intestinal interleukin-6 (IL-6) expression. In vitro studies confirmed that HO-1, ZO-1 and occludin were overex-pressed in HO-1-transfected Caco-2 cells, while decreased in the short hairpin HO (sh-HO-1) group. JSH-23 significantly increased occludin expression in both the HO-1 overexpression and sh-HO-1 groups, compared with their respective controls. HO-1 overexpression also inhibited the nuclear translocation of NF-κB p65 after lipopolysaccharide (LPS) treatment. Additionally, phospho-p65 expression in sh-HO-1 cells was significantly increased compared with that of the HO-1 overexpression group. In conclusion, HO-1 and CORM-2 improved intestinal epithelial barrier function in BDL-induced cholestatic liver injury mainly by restoring TJ, reducing cell apoptosis and intestinal inflammation. HO-1 exerts a protective effect, which is partially correlated with the regulation of NF-κB.

Notes

Acknowledgments

The present study was supported by grants from the National Natural Science Foundation of China (No. 81670479) and the Liaoning Provincial Research Program (No. 2016010223-301).

Supplementary material

10020_2017_2301215_MOESM1_ESM.pdf (2 mb)
Supplementary material, approximately 2.01 MB.

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Authors and Affiliations

  • Lijing Zhang
    • 1
  • Zhenling Zhang
    • 1
  • Bojia Liu
    • 1
  • Yanling Jin
    • 2
  • Yan Tian
    • 3
  • Yi Xin
    • 4
  • Zhijun Duan
    • 1
  1. 1.Department of GastroenterologyFirst Affiliated Hospital of Dalian Medical UniversityDalianChina
  2. 2.Department of PathologyFirst Affiliated Hospital of Dalian Medical UniversityDalianChina
  3. 3.College of PharmacyDalian Medical UniversityDalianChina
  4. 4.Department of Biochemistry and Molecular BiologyDalian Medical UniversityDalianChina

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