S1736 EP4 Receptor Blockade Inhibits Epithelial Ion Secretion Induced By PGE2, TNFα and Il1β in Human Colon

Abstract

Introduction: Increased levels of proand anti-inflammatory cytokines were observed in various segments of histologically intact small intestines in animal models of acute and chronic colitis. We recently demonstrated that these cytokines are produced de novo shortly after the induction of colitis. The trigger for this upregulation is not known. Aim: To study the possible neural involvement in the synthesis of inflammatory cytokines in remote areas from the ulcer site in rat models of colitis. Methods: Colitis was induced by rectal instillation of trinitrobenzenesulphonic acid (TNBS) or iodoacetamide in adult Sprague-Dawley rats. The capsaicin sensitive primary afferents (CSPA) were ablated using subcutaneous injections of capsaicin at time 0 (25mg/kg), 8 and 32 hours (50mg/kg). Using real time PCR, TNF-α and IL-10 mRNA expression was measured in mucosal scrapings of the duodenum, jejunum, ileum and colon at different time intervals after induction of colitis. Results: TNF-α mRNA expression increased by 3-40 times in the different intestinal segments (p<0.05) 48h after iodoacetamide induced colitis. CSPA ablation completely inhibited this upregulation in the small intestine but not in the colon. Similar results were obtained in TNBS induced colitis. Intestinal IL-10 mRNA expression increased by 6-43 times (p<0.01) 48h after iodoacetamide administration. This increase was abolished in rats subjected to CSPA ablation except in the colon where IL-10 further increased by 2 times (p<0.05). In TNBS group, there was respectively a 4-12 and 4-7 folds increase of small intestinal IL-10 mRNA expression at 1 and 21 days after colitis induction (both p<0.01). This increase was not observed in rats pretreated with capsaicin. Both capsaicin treated and untreated rats elicited a similar visual ulcer score after colitis induction. Conclusion: Intestinal CSPA fibers play a key role in the induction of a de novo synthesis of inflammatory cytokines in intestinal segments distant from the site of colitis. The study was supported by the medical practice plan (MPP) and university research board (URB), American University of Beirut-Lebanon.