Inhibition Of Spontaneous Colitis Development In Interleukin-10 Knockout Mice By Soluble Epoxide Hydrolase Inhibitor

Inflammatory bowel disease (IBD) is a longstanding idiopathic inflammatory process and arachidonic acid metabolic pathway plays an important role in inflammatory cell recruitment and process. Epoxyeicosanoids acid (EET) has various physiological functions including anti‐inflammation effects, angiogenesis, and cell proliferation. EETs can be catalyzed to DHETs by soluble epoxide hydrolase (sEH) that deactivates EET biologic functions. Thus, targeting sEH would be novel approach for anti‐inflammation. In the present study, we tested the effects of sEH inhibitor AUDA‐nBE and 1471 agents on spontaneous colitis development in IL‐10 knockout mice. AUDA‐nBE was administered through intramuscular injection (10 and 20 mg/kg/day) and 1471 was given through drinking fluid (1.25 and 2.5 mg/kg/day). In IL‐10 KO control mice (n=10), colonic inflammation exhibited ulceration and transmural inflammatory cell infiltration in the right colon and number of ulcer formation was 2.3 ± 2.1. In the mice treated with AUDA‐nBE (n=10/group), significant reduction of ulcer formation was observed with number of ulcer 0.7 ± 0.9 for low dose and 0.4 ± 0.7 for high dose (p<0.01). Incidence of ulcer formation was also significantly inhibited (75% ulcer incidence vs. 50% and 30%, respectively, p<0.05). Similar results were also observed for mice treated with 1471 compound. Further mechanistic studies using immunohistochemical approaches showed that sEH inhibitor markedly suppressed macrophage activity and numbers, iNOS expression and its mediated nitrotyrosine formation in the colon. This study indicates that the sEH inhibitor may have a potential to serve as an anti‐IBD agent. (supported by NIH R01‐CA104741)