title: Soluble epoxide hydrolase gene deficiency or inhibition attenuates chronic active inflammatory bowel disease in IL-10(-/-) mice.
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.
  
  
  OBJECTIVE
  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-γ, TNF-α, and MCP-1, as well VCAM-1 and NF-kB/IKK-α 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 LTB(4) and 5-HETE.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: Wanying
authors.initials: W
authors.lastname: Zhang
authors.forename: Allison L
authors.initials: AL
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Liao
authors.forename: Haonan
authors.initials: H
authors.lastname: Li
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.forename: Yeon Tae
authors.initials: YT
authors.lastname: Chung
authors.forename: Han
authors.initials: H
authors.lastname: Bai
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Matkowskyj
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Yang
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D002908:Chronic Disease; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010894:Piroxicam / Q000633:toxicity; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D016753:Interleukin-10; D010894:Piroxicam; D014508:Urea; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse