title: 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.
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D015232:Dinoprostone; D004848:Epithelium / Q000187:drug effects; D005260:Female; D007213:Indomethacin / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008084:Lipoxygenase / Q000378:metabolism; D011458:Prostaglandins E / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000378:metabolism
chemical_list: D011458:Prostaglandins E; D004247:DNA; D008084:Lipoxygenase; D015232:Dinoprostone; D001241:Aspirin; D013936:Thymidine; D007213:Indomethacin