Role of cyclooxygenase-2 in the healing of gastric ulcers in rats.
To elucidate the role of cyclooxygenase (COX)-2 in ulcer healing, we compared the effects of NS-398 (COX-2-selective inhibitor) and indomethacin (nonselective COX inhibitor) on the healing of acetic acid-induced gastric ulcers in rats. Prostaglandin E2 (PGE2) production was elevated in ulcerated tissue, but remained unaffected in intact tissue. COX-2 mRNA was only detected in the ulcerated tissue, in which the COX-2 protein was found in fibroblasts, macrophages/monocytes and granulocytes. In contrast, COX-1 mRNA expression was not affected by ulceration. In an in vitro study, the increased PGE2 production was inhibited by NS-398; this had no effect on PGE2 production in the intact tissue. When NS-398 and indomethacin were administered to rats, 3 and 6 mg/kg NS-398 only reduced PGE2 production in the ulcerated tissue, but 10 mg/kg NS-398 and 0.5 to 2 mg/kg indomethacin inhibited the production in both the ulcerated and intact tissues. The healing of gastric ulcers was significantly impaired by 3 to 10 mg/kg NS-398 and 1 and 2 mg/kg indomethacin. The delay in ulcer healing was associated with the inhibition of PGE2 production in the ulcerated tissue. As observed upon histological analysis, regeneration of the mucosa, maturation of the ulcer base and angiogenesis in the base were significantly prevented by 6 mg/kg NS-398 and 2 mg/kg indomethacin, although the inhibitory effect of NS-398 was weaker than that of indomethacin. These results clearly indicate that COX-2 plays an important role in the healing of gastric ulcers in rats.
Shigeta
J
J
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
Takahashi
S
S
Okabe
S
S
D000818:Animals; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D013276:Stomach Ulcer / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D013449:Sulfonamides / Q000494:pharmacology
D007527:Isoenzymes; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin