Soluble Epoxide Hydrolase: A Novel Biomarker and Therapeutic Target of Ulcerative Colitis and Colitis-Induced Carcinogenesis
SD Norwood, J Liao, C Tsai, BD Hammock, G-Y Yang. Northwestern University, Chicago, IL; University of California at Davis, Davis, CA
Background: Cytochrome p450 mediated epoxyeicosatrienoic acids(EETs) show strong anti-inflammatory activity and are deactivated by the enzyme soluble epoxide hydrolase(sEH) by conversion to DHETs. sEH may play an important role in inflammatory diseases such as ulcerative colitis (UC), and targeting sEH could be a novel approach for decreasing inflammation. In the present study, we determine the expression pattern of sEH in UC, UC-induced dysplasia and carcinoma, and the effect of an sEH inhibitor on inflammation in a mouse colitis model.
Design: Tissue microarrays of 180 patients with UC(n=72), colitis-induced dysplasia(n=54), and colitis-induced carcinoma(n=54) were established. Adjacent normal colonic tissue was also identified in these patients(n=79). Avidin-biotin-peroxidase approach was used with anti-sEH antibody and proper +/- controls. sEH staining positivity was evaluated for its intensity on a scale of 0-3+ and compared with positive controls(liver & kidney). The effects of the sEH inhibitor AUDA-nBE on spontaneous colitis development in IL-10 KO mice were determined. AUDA-nBE was administered intramuscularly(10 and 20 mg/kg/day). Inflammatory activity and the incidence and number of ulcer formation in the colon was analyzed histopathologically and immunohistochemically.
Results: sEH showed distinct expression in the microarray samples. Normal colon displayed positivity in 39.1% (n=79), mainly in the focally reactive epithelia. In UC, 74.6%(n=72) displayed positivity, extensively expressed in the hyperplastic epithelia. 88.2%(n=54) of colitis-induced dysplasia and 93.9%(n=54) of colitis-induced carcinoma displayed positivity. Markedly increased sEH staining intensity was observed in UC, UC-induced dysplasia and carcinoma and the average staining intensity of sEH was 0.43 in normal glands, 0.89 in UC, 1.29 in dysplasia, and 1.31 in carcinoma. In the colitis mouse model, IL-10 KO control mice (n=10) formed 2.3 +/-2.1 ulcers with 75% ulcer incidence. The AUDA-nBE treated mice (n=10), formed 0.7+/-0.9 ulcers for low dose and 0.4 +/- 0.7 ulcers for high dose (p<0.01), with 50% and 30% ulcer incidence, respectively (p<0.05). Myeloperoxidase-labeled inflammatory cells were also significantly decreased in the AUDA-nBE group.
Conclusions: Our results indicate that sEH may play an important role in UC and UC-induced carcinogenesis, and sEH inhibition leads to a significant decrease in ulcer formation and inflammatory activity in UC.
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 71, Wednesday Morning