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P097. The efficacy of benzoxazole derivatives (B-98) as 5-lipooxygenase inhibitor and the change of T cell profiles in acute murine colitis model

E.M. Song1, S.-A. Jung1, J.-S. Lee2, H.-I. Kim1, S.-Y. Yoon1, W.Y. Cho1, S.-E. Kim1, H.-K. Jung1, K.-N. Shim1, T.H. Kim1, S.Y. Yi1, K. Yoo1, I.H. Moon1, 1Ewha Medical Research Institute. Ewha Womans University School of Medicine, Department of Internal Medicine, Seoul, South Korea, 2Asan Medical Center, Health Promotion Center, Seoul, South Korea

Background

Amplification of mucosal inflammatory response in inflammatory bowel disease (IBD) is likely to be controlled by many mediators including leukotrienes. The unique role of enzyme 5-lipoxygenase (5-LO) in the production of leukotrienes makes it a therapeutic target for IBD. The aim of this study was to evaluate the effects of B-98, a newly synthesized benzoxazole derivative and a novel 5-lipoxygenase inhibitor, in mice model of IBD induced by dextran sulfate sodium (DSS). We also investigated the effect of B-98 on the Th (helper T) cell and Treg (regulatory T) cell profiles.

Methods

Seven to eight week old C57BL/6 mice were randomly assigned to 3 groups: normal control, DSS colitis group (DSS + saline), B-98 group (DSS + B-98 20 mg/kg). For the induction of acute colitis, the mice were treated with 3% DSS for seven days. B-98 diluted in dimethyl sulfoxide was administered simultaneously with DSS from day 1 to 7 by intraperitoneal route. On day 8, the mice were sacrificed and proximal and distal colonic specimens were obtained. The severity of the colitis was assessed via the disease activity index (DAI), colon length, and histopathologic grading. The production of cytokines IL-6 and TNF-α was determined by RT-PCR. Th cells from the lamina propia were examined for the expression of IFN-γ (Th1 cell), IL-4 (Th2 cell), IL-9 (Th9 cell), IL-17 (Th17 cell) and Foxp3 (Treg cell) using intracellular cytometry.

Results

The mice in the DSS colitis group suffered hematochezia from day 4 and showed marked colonic shortening compared with the normal control group (82.5 vs 49.5 mm, p < 0.01). The B-98 group showed lower DAI, less shortening of the colon length and lower histopathologic grading (p < 0.01) compared with the DSS colitis group. The expression of inflammatory cytokine IL-6 in colonic tissue was significantly lower in the B-98 groups than in the DSS colitis group (p < 0.05). However, there were no significant differences in the TNF-α levels between the groups. The cellular profiles revealed that the Th1, Th9 and Th17 cells were elevated in the DSS colitis group and decreased in the B-98 group (p < 0.05). No significant differences were found in the Th2 or Treg cells between the groups.

Conclusion

Our results suggest that the B-98 ameliorated intestinal inflammation and reduced the IL-6 levels. B-98 may be involved with Th1, Th9 and Th17 cellular immunity in acute colitis model. Further evaluations would be needed to elucidate the exact effects of B-98.