Sustained increase in the proliferation of rat colonic mucosa during chronic treatment with aspirin

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.