TY - JOUR
T1 - Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic
AU - Masferrer, Jaime L.
AU - Zweifel, Ben S.
AU - Manning, Pamela T.
AU - Hauser, Scott D.
AU - Leahy, Kathleen M.
AU - Smith, Walter G.
AU - Isakson, Peter C.
AU - Seibert, Karen
PY - 1994/4/12
Y1 - 1994/4/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0028322893&partnerID=8YFLogxK
U2 - 10.1073/pnas.91.8.3228
DO - 10.1073/pnas.91.8.3228
M3 - Article
C2 - 8159730
AN - SCOPUS:0028322893
SN - 0027-8424
VL - 91
SP - 3228
EP - 3232
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 8
ER -