Healing impairment effect of cyclooxygenase inhibitors on dextran sulfate sodium-induced colitis in rats.
We examined the effects of various cyclooxygenase (COX) inhibitors on the healing of colonic lesions induced by dextran sulfate sodium (DSS) in the rat. Colonic lesions were induced by 2.5% DSS in the drinking water for 7 days, and then the animals were fed with tap water for subsequent 7 days. Indomethacin (a nonselective COX inhibitor), SC-560 (a selective COX-1 inhibitor), or rofecoxib (a selective COX-2 inhibitor) was given orally twice daily after termination of the DSS treatment. DSS treatment caused severe colonic lesions with a decrease in body weight gain and colon length as well as an increase in myeloperoxidase activity and thiobarbituric acid reactant levels. The severity of colitis gradually reduced, with an improvement of morphological and histological alterations. Daily administration of indomethacin and rofecoxib significantly delayed the healing of colitis with deleterious influences on histological restitution as well as mucosal inflammation, while SC-560 had no effect. Although COX-1 mRNA was expressed in the colon without much alteration during the test period, the expression of COX-2 was upregulated with a peak on day 3 and decreased thereafter. The mucosal prostaglandin E2 content in the colon showed a biphasic change, in parallel with that of the COX-2 expression. The increased prostaglandin E2 production in the injured mucosa was attenuated by indomethacin and rofecoxib, but not by SC-560. These results suggest that endogenous prostaglandins produced by COX-2 play an important role in the healing of DSS-induced colonic lesions. Caution should be paid to the use of selective COX-2 inhibitors as well as nonsteroidal anti-inflammatory drugs in patients with colitis.
Tsubouchi
Ryoichi
R
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
Hayashi
Shusaku
S
Aoi
Yoko
Y
Nishio
Hikaru
H
Terashima
Shun
S
Kato
Shinichi
S
Takeuchi
Koji
K
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D003106:Colon / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D051545:Cyclooxygenase 1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016264:Dextran Sulfate / Q000633:toxicity; D015232:Dinoprostone / Q000032:analysis / Q000037:antagonists & inhibitors*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology; D008297:Male; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D012333:RNA, Messenger; D016264:Dextran Sulfate; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone