MECHANISMS OF ACUTE AND CHRONIC INTESTINAL INFLAMMATION-INDUCED BY INDOMETHACIN

The objective of this study was to characterize the mechanisms of acut e and chronic intestinal mucosal injury and inflammation induced by su bcutaneously injected indomethacin (Indo). One injection of Indo (7.5 mg/kg) produced acute injury and inflammation in the distal jejunum an d proximal ileum that were maximal at three days and completely resolv ed within one week. Two daily subcutaneous injections of Indo produced a more extensive and chronic inflammation that lasted in an active fo rm in more than 75 % of the rats for at least two weeks. Epithelial in jury, as measured by enhanced mucosal permeability, was significantly elevated only at one day in the acute model (one injection) but was pe rsistently elevated in the chronic model (two injections). Bile duct l igation completely attenuated increased mucosal permeability in the ac ute model, however, depletion of circulating neutrophils had no effect . Neither Indo (0-0.1 mg/ml) nor normal bile was cytotoxic to cultured rat intestinal epithelial cells; however, they synergistically promot ed significant cytotoxicity. Bile collected from rats treated with Ind o was cytotoxic towards the epithelial cells in a dose-dependent manne r. Sulfasalazine and metronidazole (100 mg/kg/day, both) attenuated en hanced mucosal permeability in the chronic model. Massive bacterial tr anslocation into the mesenteric lymph nodes, liver, and spleen followi ng two injections of Indo was significantly attenuated by metronidazol e. We conclude that: (1) a single injection of Indo produces acute int estinal mucosal injury and inflammation that resolve completely within three to seven days, whereas two daily injections of Indo produce bot h acute and chronic injury and inflammation, (2) enterohepatic circula tion of Indo is important in promoting the acute phases of injury and inflammation, (3) circulating neutrophils do not play a role in the pa thogenesis of this model, and (4) endogenous bacteria play an importan t role in exacerbating and/or perpetuating the chronic phases of injur y and inflammation.