Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic.
We have examined the role of cyclooxygenase 2 (COX-2) in a model of inflammation in vivo. Carrageenan administration to the subcutaneous rat air pouch induces a rapid inflammatory response characterized by high levels of prostaglandins (PGs) and leukotrienes in the fluid exudate. The time course of the induction of COX-2 mRNA and protein coincided with the production of PGs in the pouch tissue and cellular infiltrate. Carrageenan-induced COX-2 immunoreactivity was localized to macrophages obtained from the fluid exudate as well as to the inner surface layer of cells within the pouch lining. Dexamethasone inhibited both COX-2 expression and PG synthesis in the fluid exudate but failed to inhibit PG synthesis in the stomach. Furthermore, NS-398, a selective COX-2 inhibitor, and indomethacin, a nonselective COX-1/COX-2 inhibitor, blocked proinflammatory PG synthesis in the air pouch. In contrast, only indomethacin blocked gastric PG and, additionally, produced gastric lesions. These results suggest that inhibitors of COX-2 are potent antiinflammatory agents which do not produce the typical side effects (e.g., gastric ulcers) associated with the nonselective, COX-1-directed antiinflammatory drugs.
Masferrer
J L
JL
Searle Inflammatory Diseases Research, G. D. Searle, St. Louis, MO 63167.
Zweifel
B S
BS
Manning
P T
PT
Hauser
S D
SD
Leahy
K M
KM
Smith
W G
WG
Isakson
P C
PC
Seibert
K
K
D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents; D002351:Carrageenan; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D005753:Gastric Mucosa / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000201:enzymology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008969:Molecular Sequence Data; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013449:Sulfonamides / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D009578:Nitrobenzenes; D011453:Prostaglandins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D003907:Dexamethasone; D002351:Carrageenan; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin