Soluble epoxide hydrolase gene deficiency or inhibition attenuates chronic active inflammatory bowel disease in IL-10(2/2) mice

Wanying Zhang, Allison L. Yang, Jie Liao, Haonan Li, Hua Dong, Yeon Tae Chung, Han Bai, Kristina A. Matkowskyj, Bruce D. Hammock, Guang Yu Yang

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Background Soluble epoxide hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids (EETs) into their much less active dihydroxy derivatives dihydroxyeicosatrienoic acids. Thus, targeting sEH would be important for inflammation. Aims To determine whether knockout or inhibition of sEH would attenuate the development of inflammatory bowel disease (IBD) in a mouse model of IBD in IL-10(-/-) mice. Methods Either the small molecule sEH inhibitor trans/- 4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) or sEH knockout mice were used in combination with IL-10(-/-) mice. t-AUCB was administered to mice in drinking fluid. Extensive histopathologic, immunochemical, and biochemical analyses were performed to evaluate effect of sEH inhibition or deficiency on chronic active inflammation and related mechanism in the bowel. Results Compared to IL-10 (-/-) mice, sEH inhibition or sEH deficiency in IL-10(-/-) mice resulted in significantly lower incidence of active ulcer formation and transmural inflammation, along with a significant decrease in myeloperoxidase-labeled neutrophil infiltration in the inflamed bowel. The levels of IFN-c, TNF-a, and MCP-1, as well VCAM-1 and NF-kB/IKK-a signals were significantly decreased as compared to control animals. Moreover, an eicosanoid profile analysis revealed a significant increase in the ratio of EETs/DHET and EpOME/DiOME, and a slightly down-regulation of inflammatory mediators LTB4 and 5-HETE. Conclusion These results indicate that sEH gene deficiency or inhibition reduces inflammatory activities in the IL-10 (-/-) mouse model of IBD, and that sEH inhibitor could be a highly potential in the treatment of IBD.

Original languageEnglish (US)
Pages (from-to)2580-2591
Number of pages12
JournalDigestive Diseases and Sciences
Volume57
Issue number10
DOIs
StatePublished - Oct 2012

Keywords

  • Ephx2 gene
  • IL-10 deficient mice
  • Inflammatory bowel disease
  • Oxylipin profile
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology

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    Zhang, W., Yang, A. L., Liao, J., Li, H., Dong, H., Chung, Y. T., Bai, H., Matkowskyj, K. A., Hammock, B. D., & Yang, G. Y. (2012). Soluble epoxide hydrolase gene deficiency or inhibition attenuates chronic active inflammatory bowel disease in IL-10(2/2) mice. Digestive Diseases and Sciences, 57(10), 2580-2591. https://doi.org/10.1007/s10620-012-2217-1