Aggravation by selective COX-1 and COX-2 inhibitors of dextran sulfate sodium (DSS)-induced colon lesions in rats.
We examined the effect of cyclooxygenase (COX) inhibitors on dextran sulfate sodium (DSS)-induced ulcerative colitis in rats and investigated the role of COX isozymes in the pathogenesis of this model. Experimental colitis was induced by treatment with 2.5% DSS in drinking water for 6 days. Indomethacin (a nonselective COX inhibitor), SC-560 (a selective COX-1 inhibitor), or celecoxib (a selective COX-2 inhibitor) was given PO twice daily for 6 days, during the first 3 or last 3 days of the experimental period. Daily treatment with 2.5% DSS for 6 days caused damage to the colon, with a decrease in body weight gain and colon length as well as an increase of myeloperoxidase (MPO) activity. All COX inhibitors given for 6 days significantly worsened the severity of DSS-induced colonic damage with increased MPO activity. The aggravation was also observed by SC-560 given for the first 3 days or by celecoxib given for the last 3 days. The expression of COX-2 mRNA in the colon was upregulated on day 3 during DSS treatment, with significant increase of prostaglandin E(2) PGE(2) production. The PGE(2) content on day 3 during DSS treatment was inhibited by both indomethacin and SC-560, but not by celecoxib; on day 6 it was suppressed by both indomethacin and celecoxib, but not SC-560. These results suggest that endogenous prostaglandins (PGs) afford protection against colonic ulceration, yet the COX isozyme responsible for the production of PGs differs depending on the stage of ulceration; COX-1 in the early stage and COX-2 in the late stage.
Okayama
Mitsuaki
M
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
Hayashi
Shusaku
S
Aoi
Yoko
Y
Nishio
Hikaru
H
Kato
Shinichi
S
Takeuchi
Koji
K
D000818:Animals; D002318:Cardiovascular Diseases; D000068579:Celecoxib; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051545:Cyclooxygenase 1 / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D016264:Dextran Sulfate / Q000633:toxicity; D015232:Dinoprostone / Q000096:biosynthesis; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D007213:Indomethacin / Q000627:therapeutic use; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D010952:Plasma Substitutes / Q000633:toxicity; D011720:Pyrazoles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013053:Spectrophotometry; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome
D016861:Cyclooxygenase Inhibitors; D010952:Plasma Substitutes; D011720:Pyrazoles; D012333:RNA, Messenger; C115461:SC 560; D013449:Sulfonamides; D016264:Dextran Sulfate; D009195:Peroxidase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone; D007213:Indomethacin