A novel diamino-pyridine derivative (IS-741) attenuates rat ileitis induced by trinitrobenzene sulfonic acid

Background, The etiology and pathogenesis of inflammatory bowel disease remain unknown. However, neutrophil infiltration into the inflammatory lesion is an important process in inflammatory bowel disease. In this study, we used rat trinitrobenzene sulfonic acid (TNBS) ileitis as a Crohn's disease model, and investigated the effects of oral IS-741 (which inhibits the expression of Mac-1, a cell adhesion molecule) on leukocyte-endothelial interactions. Methods. Rat ileitis was induced by the intraluminal injection of a TNBS solution (160mg/kg in 50% ethanol) at a site 10cm proximal to the ileocecal valve. The rats then received oral IS-741 (50mg/kg) or saline for 7 days. On the day 8 after the initial administration of IS-741 or saline, we determined the visible damage score, and assessed myeloperoxidase (MPO) activity. Concentrations of cytokines in the ileum, such as interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) were assayed by enzyme-linked immunosorbent assay (ELISA). We also investigated the infiltration of polymorphonuclear cells and Mac-1 positive cells by histological examinations. Results. The administration of IS-741 resulted in a significant reduction of the visible damage score, myeloperoxidase (MPO) activity, and mucosal IL-8 levels in the ileum as compared with the saline administration. IS-741 also dramatically reduced the infiltration of polymorphonuclear cells and Mac-1 positive cells into the inflamed lesions. Conclusions. These results indicate that the oral administration of IS-741 inhibits neutrophil infiltration into inflamed lesions, and is effective for attenuating rat TNBS ileitis. This new anti-inflammatory agent may be beneficial for the treatment of inflammatory bowel disease.