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.