Abstract

The effects of indomethacin and aspirin on colonic epithelial proliferative activity, colonic prostaglandin synthesis, and colonic mucosal cyclic adenosine 3′,5′-monophosphate content were examined. Administration of indomethacin (3 mg/kg day, s.c.) for 2 wk suppressed ex vivo colonic prostaglandin E2 production by 50% and increased [3H]thymidine incorporation into mucosal DNA in vivo, but induced colonic inflammation. Higher doses of indomethacin were toxic and associated with high mortality. By contrast, administration of aspirin (50 mg/kg · day, s.c.) for 2–20 wk suppressed colonic prostaglandin E2 production by 97% and was unassociated with colonic inflammation or systemic toxicity. Suppression of colonic prostaglandin E2 production was associated with a sustained stimulation of [3H]thymidine incorporation into colonic mucosal deoxyribonucleic acid (2–20 wk) and an increase in the [3H]thymidine labeling index when examined at 20 wk. Basal cyclic adenosine 3′,5′monophosphate content of colonic mucosa was markedly reduced in aspirin-treated rats. Moreover, addition of dimethyl prostaglandin E2 or 8-Br-cyclic adenosine 3′,5′-monophosphate suppressed the elevated levels of [3H]thymidine incorporation into mucosal deoxyribonucleic acid in incubated colonic segments from aspirin-treated rats. The results demonstrate that sustained suppression of colonic prostaglandin synthesis by aspirin is associated with a persistent increase in colonic epithelial proliferative activity. They support a role for local colonic prostaglandin synthesis as a negative modulator of epithelial growth, possibly mediated through increases in colonic mucosal cyclic adenosine 3′,5′-monophosphate.

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