Inflammatory bowel disease (IBD) is an umbrella term used to describe two distinct clinical conditions, ulcerative colitis and Crohn's disease. In 2001, the number of prevalent cases of IBD totaled 547,720 and 1,122,300, respectively, in the major pharmaceutical markets. The total sales of pharmacologic therapies to treat IBD in these markets were estimated as $516.8 million in 1998. This figure is expected to increase by 10% each year to $836 million in 2003, and by 3% each year afterward to $970.4 million in 2008. Classic therapies of IBD have centered on the use of 5-ASA agents that prevent the synthesis of prostaglandins. Prostaglandins can however play a cytoprotective role and indeed the dependence of the gastrointestinal tract on these eicosanoids to maintain mucosal integrity has driven the recent development of mucosa sparing COX-2 inhibitors. Likewise the development of specific prostaglandin receptor agonists could have potential in the treatment of disease associated with disruption of the intestinal barrier such as IBD. The potential of this approach has grown with our greater understanding of the various subtypes of prostanoid receptors. Japanese researchers have investigated the sensitivity of mice deficient in 8 known receptor subtypes to dextran sodium sulfate (DSS), a commonly employed inducer of experimental colitis. Among the prostanoid receptor-deficient mice, only EP4-deficient mice and not mice deficient in DP, EP1, EP2, EP3, FP, IP, or TP developed severe colitis with 3% DSS treatment, which induced only marginal colitis in wild-type mice. This phenotype was mimicked in wild-type mice by administration of an EP4-selective antagonist (AE3-208). The EP4 deficiency impaired mucosal barrier function and induced epithelial loss, crypt damage, and aggregation of neutrophils and lymphocytes in the colon. Conversely, administration of an EP4-selective agonist (AE1-734) to wild-type mice ameliorated severe colitis normally induced with 7% DSS, while that of AE3-208 suppressed recovery from colitis and induced significant proliferation of CD4+ T cells. In vitro AE3-208 enhanced and AE1-734 suppressed the proliferation and Th1 cytokine production of lamina propria mononuclear cells from the colon. DNA microarray analysis revealed elevated expression of genes associated with immune response and reduced expression of genes with mucosal repair and remodeling in the colon of EP4-deficient mice. EP4 thus appears to maintain intestinal homeostasis by supporting mucosal integrity and downregulating immune response. The development of specific EP4 agonists could thus be of considerable benefit to IBD sufferers.

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