The ability of nonsteroidal anti-inflammatory drugs to exacerbate experimental
colitis, and the possible contributions of the "shunting" of arachidonate via the
5-lipoxygenase pathway, were investigated using a rat model in which
colitis was induced by intracolonic administration of trinitrobenzene
sulfonic acid in a vehicle of 50%
ethanol. Twice daily treatment with
indomethacin (0.1-1 mg/kg SC) during the first week after trinitrobenzene
sulfonic acid/
ethanol administration resulted in dose-dependent increases in the severity of
colitis and in the incidence of mortality. Mortality was not observed in vehicle-treated colitic rats or in normal rats treated with
indomethacin. Similar exacerbation of
colitis was observed in rats treated with
naproxen (5 mg/kg). Whereas treatment with a
5-lipoxygenase inhibitor,
PF-5901 (100 mg/kg PO), resulted in a significant reduction of the severity of
colitis, concomitant administration of
PF-5901 and
indomethacin (0.5 mg/kg SC) did not inhibit the exacerbative effects of the
indomethacin in this model. In separate studies, administration of
indomethacin was found to significantly increase colonic
myeloperoxidase activity (a measure of tissue granulocyte numbers) and suppress colonic
prostaglandin E2 synthesis, while not significantly affecting colonic
leukotriene B4 synthesis. The effect on
myeloperoxidase activity was seen during the period 21-24 hours after trinitrobenzene
sulfonic acid ethanol administration, but not during the period 45-48 hours after induction of
colitis. In in vitro studies using samples of inflamed colon and in vivo studies in which colonic
eicosanoid production was measured by colonic dialysis, inhibition of
prostaglandin E2 synthesis was not accompanied by significant changes in
leukotriene B4 synthesis. These results suggest that inhibitors of colonic
prostaglandin synthesis can markedly exacerbate
colitis, and that this effect is unrelated to alterations in colonic
leukotriene B4 synthesis. Endogenous
prostaglandins may exert anti-inflammatory effects during the acute stages of
colitis.