Tu1239 Prophylactic Effects of Proton Pump Inhibitors on NSAIDs Induced Small Intestinal Injury in Rats

Abstract

Background and Aim: Non-steroidal anti-inflammatory drugs (NSAIDs) is known to cause mucosal injury in not only the upper gastrointestine but also the small intestine. Proton pump inhibitors(PPIs) are useful for the treatment of upper gastrointestinal mucosal injuries induced by NSAIDs. However, it was reported that some kinds of PPI exacerbate NSAIDsinduced small intestinal injury. The mechanism of NSAIDs-induced small intestinal injury is unclear and acid is not related to its mucosal injury. In this study, we confirmed effects of each PPIs which suppress gastric acid secretion for indomethacin(IM)-induced small intestinal mucosal injury and investigated the molecular mechanism of PPI which protected small intestinal injury induced by indomethacin. Methods: (In vivo study) Male SD rats were orally administered IM (10 mg/kg) and their small intestines were resected 24 hours later. We measured the ulcer index, MPO activity, iNOS-mRNA expression, and bacterial count. PPIs were orally administered 30 min before IM administration:lansoprazole (30 mg/ kg or 100 mg/kg) or omeprazole (30 mg/kg or 100 mg/kg). In addition, we investigated the effects of lansoprazole or omeprazole on heme oxygenase-1(HO-1), which is deeply involved in mucosal protection. (in vitro study) We confirmed the expression of HO-1 by realtime PCR andWestern Blotting in IEC-6 stimulated lansoprazole, IM, or lansoprazole+IM. We also confirmed how these drugs affect cell mass culturing by MTT assay and examined participation of NF-E2 related factor 2(Nrf2). Results: (1)Among PPIs, only lansoprazole inhibited small intestinal lesions. (2)Lansoprazole inhibited iNOS-mRNA expression, MPO activity, and the bacterial count in the infiltrated intestinal mucosa. (3) The amount of HO1 protein in the intestinal mucosa was significantly increased by lansoprazole but not by omeprazole. Prior administration of carbonmonoxide (CO)-releasingmolecule-2 significantly reduced the severity of these lesions, suggesting that lansoprazole ameliorates small intestinal ulceration through upregulation of HO-1/CO. (4) IM induced the expression of HO-1 at maximum 6hours, lansoprazole at 12hours, and lansoprazole+IM at 12hours after administration of drugs in IEC-6. Lansoprazole induced the expression Nrf2 at 6hours later. Knock down of Nrf2 decreased the preventive effect of lansoprazole in IEC-6. Conclusion: Among PPIs, only lansoprazole suppressed IM-induced small intestinal injury. Lansoprazole induced the expression of HO-1 and the protective effect of lansoprazole against IM-induced small intestinal injury was related to HO-1 inducted by Nrf2.