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

Overview

Journal Mol Med

Publisher Biomed Central

Specialties General Medicine
Molecular Biology

Date 2017 Aug 15

PMID 28805232

Citations 12

Authors

Lijing Zhang

Zhenling Zhang

Bojia Liu

Yanling Jin

Yan Tian

Yi Xin

Zhijun Duan

Affiliations

Soon will be listed here.

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 overexpressed in HO-1-transfected Caco-2 cells, while decreased in the 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.

Citing Articles

Heme Oxygenase-1 and Its Role in Colorectal Cancer.

Fahrer J, Wittmann S, Wolf A, Kostka T Antioxidants (Basel). 2023; 12(11).

PMID: 38001842 PMC: 10669411. DOI: 10.3390/antiox12111989.

The Intestinal Redox System and Its Significance in Chemotherapy-Induced Intestinal Mucositis.

Yu Q, Zhang H, Guo Y, Han B, Jiang P Oxid Med Cell Longev. 2022; 2022:7255497.

PMID: 35585883 PMC: 9110227. DOI: 10.1155/2022/7255497.

Fecal Supernatant from Adult with Autism Spectrum Disorder Alters Digestive Functions, Intestinal Epithelial Barrier, and Enteric Nervous System.

Gonzales J, Marchix J, Aymeric L, Le Berre-Scoul C, Zoppi J, Bordron P Microorganisms. 2021; 9(8).

PMID: 34442802 PMC: 8399841. DOI: 10.3390/microorganisms9081723.

HO-1/CO Maintains Intestinal Barrier Integrity through NF-B/MLCK Pathway in Intestinal HO-1 Mice.

Zhang Z, Zhang L, Zhang Q, Liu B, Li F, Xin Y Oxid Med Cell Longev. 2021; 2021:6620873.

PMID: 34104309 PMC: 8159651. DOI: 10.1155/2021/6620873.

Potential Mechanisms Linking Food-Derived MicroRNAs, Gut Microbiota and Intestinal Barrier Functions in the Context of Nutrition and Human Health.

Diez-Sainz E, Lorente-Cebrian S, Aranaz P, Riezu-Boj J, Martinez J, Milagro F Front Nutr. 2021; 8:586564.

PMID: 33768107 PMC: 7985180. DOI: 10.3389/fnut.2021.586564.

References

Froh M, Conzelmann L, Walbrun P, Netter S, Wiest R, Wheeler M . Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats. World J Gastroenterol. 2007; 13(25):3478-86. PMC: 4146784. DOI: 10.3748/wjg.v13.i25.3478. View

Mir H, Meena A, Chaudhry K, Shukla P, Gangwar R, Manda B . Occludin deficiency promotes ethanol-induced disruption of colonic epithelial junctions, gut barrier dysfunction and liver damage in mice. Biochim Biophys Acta. 2016; 1860(4):765-74. PMC: 4776745. DOI: 10.1016/j.bbagen.2015.12.013. View

Szabo G . Gut-liver axis in alcoholic liver disease. Gastroenterology. 2014; 148(1):30-6. PMC: 4274189. DOI: 10.1053/j.gastro.2014.10.042. View

Oshima T, Miwa H . Gastrointestinal mucosal barrier function and diseases. J Gastroenterol. 2016; 51(8):768-78. DOI: 10.1007/s00535-016-1207-z. View

He F, Peng J, Deng X, Yang L, Camara A, Omran A . Mechanisms of tumor necrosis factor-alpha-induced leaks in intestine epithelial barrier. Cytokine. 2012; 59(2):264-72. DOI: 10.1016/j.cyto.2012.04.008. View

Barikbin R, Neureiter D, Wirth J, Erhardt A, Schwinge D, Kluwe J . Induction of heme oxygenase 1 prevents progression of liver fibrosis in Mdr2 knockout mice. Hepatology. 2011; 55(2):553-62. DOI: 10.1002/hep.24711. View

Wang P, Koyama Y, Liu X, Xu J, Ma H, Liang S . Promising Therapy Candidates for Liver Fibrosis. Front Physiol. 2016; 7:47. PMC: 4754444. DOI: 10.3389/fphys.2016.00047. View

Zhang S, Zheng S, Wang X, Shi Q, Wang X, Yuan S . Carbon Monoxide-Releasing Molecule-2 Reduces Intestinal Epithelial Tight-Junction Damage and Mortality in Septic Rats. PLoS One. 2016; 10(12):e0145988. PMC: 4697838. DOI: 10.1371/journal.pone.0145988. View

Wang Q, Du J, Duan Z, Guo S, Sun X, Liu Z . Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation. World J Gastroenterol. 2013; 19(19):2921-34. PMC: 3660817. DOI: 10.3748/wjg.v19.i19.2921. View

10.

Somi M, Kalageychi H, Hajipour B, Musavi G, Khodadadi A, Shokri N . Lipoic acid prevents hepatic and intestinal damage induced by obstruction of the common bile duct in rats. Eur Rev Med Pharmacol Sci. 2013; 17(10):1305-10. View

11.

Su L, Shen L, Clayburgh D, Nalle S, Sullivan E, Meddings J . Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. Gastroenterology. 2008; 136(2):551-63. PMC: 2712351. DOI: 10.1053/j.gastro.2008.10.081. View

12.

Cai S, Ouyang X, Chen Y, Soroka C, Wang J, Mennone A . Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight. 2017; 2(5):e90780. PMC: 5333973. DOI: 10.1172/jci.insight.90780. View

13.

Mehta G, Mookerjee R . Breaking bad - the two sides of gut microbiota in portal hypertension. Liver Int. 2014; 34(9):1295-7. DOI: 10.1111/liv.12598. View

14.

Kundu S, Kumar S, Bajaj A . Cross-talk between bile acids and gastrointestinal tract for progression and development of cancer and its therapeutic implications. IUBMB Life. 2015; 67(7):514-23. DOI: 10.1002/iub.1399. View

15.

Chazouilleres O . Novel Aspects in the Management of Cholestatic Liver Diseases. Dig Dis. 2016; 34(4):340-6. DOI: 10.1159/000444544. View

16.

Zahiri H, Perrone E, Strauch E . Bile salt supplementation acts via the farnesoid X receptor to alleviate lipopolysaccharide-induced intestinal injury. Surgery. 2011; 150(3):480-9. DOI: 10.1016/j.surg.2011.07.008. View

17.

Ljubuncic P, Tanne Z, Bomzon A . Evidence of a systemic phenomenon for oxidative stress in cholestatic liver disease. Gut. 2000; 47(5):710-6. PMC: 1728111. DOI: 10.1136/gut.47.5.710. View

18.

Motterlini R, Otterbein L . The therapeutic potential of carbon monoxide. Nat Rev Drug Discov. 2010; 9(9):728-43. DOI: 10.1038/nrd3228. View

19.

Xiao Y, Yan W, Cao Y, Yan J, Cai W . Neutralization of IL-6 and TNF-α ameliorates intestinal permeability in DSS-induced colitis. Cytokine. 2016; 83:189-192. DOI: 10.1016/j.cyto.2016.04.012. View

20.

Ridlon J, Kang D, Hylemon P, Bajaj J . Bile acids and the gut microbiome. Curr Opin Gastroenterol. 2014; 30(3):332-8. PMC: 4215539. DOI: 10.1097/MOG.0000000000000057. View