Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation

To examine the role of cyclooxygenase (COX) isozymes in prostaglandin forma tion and oxidant stress in inflammation, we administered to volunteer subje cts placebo or bolus injections of lipopolysaccharide (LPS), which caused a dose-dependent increase in temperature, heart rate, and plasma cortisol. L PS caused also dose-dependent elevations in urinary excretion of 2,3-dinor 6-keto PGF(1 alpha)(PGI-M) and 11-dehydro thromboxane B-2 (Tx-M). Platelet COX-1 inhibition by chronic administration of low-dose aspirin before LPS d id not alter the symptomatic and febrile responses to LPS, but the incremen t in urinary PGI-M and Tx-M were both partially depressed. Pretreatment wit h ibuprofen, a nonspecific COX inhibitor, attenuated the febrile and system ic response to LPS and inhibited prostanoid biosynthesis, Both celecoxib, a selective COX-2 inhibitor, and ibuprofen attenuated the pyrexial, but not the chronotropic, response to LPS, Experimental endotoxemia caused differen tial expression of the COX isozymes in monocytes and polymorphonuclear leuc ocytes ex vivo. LPS also increased urinary iPF(2 alpha)-III iPF(2 alpha)-VI , and 8,12-iso-iDF(2 alpha)-VI, isoprostane (iP) indices of lipid peroxidat ion, and none of the drugs blunted this response. These studies indicate th at (a) although COX-2 predominates, both COX isozymes are induced and contr ibute to the prostaglandin response to LPS in humans; (b) COX activation co ntributes undetectably to lipid peroxidation induced by LPS; and (c) COX-2, but not COX-I, contributes to the constitutional response to LPS in humans .