Origins of prostaglandin E2:: Involvements of cyclooxygenase (COX)-1 and COX-2 in human and rat systems

Prostaglandin (PG) E-2 is a major cyclooxygenase (COX) product at inflammatory sites where it contributes to local increases in blood flow, edema formation, and pain sensitization. Using rats in vivo and rat and human blood in vitro, we have examined the roles of COX-1 and COX-2 in the production of PGE(2). In anesthetized rats treated with bacterial lipopolysaccharide (LPS) to induce the expression of COX-2, the marked increase in PGE(2) production that followed bolus intravenous injection of arachidonic acid (3 mg kg(-1)) was strongly inhibited by diclofenac but largely unaffected by the COX-2-selective inhibitor DFP (5,5-dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-fura-none). In rat blood in vitro, aspirin strongly inhibited the production of PGE(2) that followed either acute exposure to calcium ionophore, A23187 (calcimycin) (50 muM, 15 min), or incubation with LPS for 18 h. In contrast, human whole blood only produced significant levels of PGE(2) when incubated with LPS. Rat leukocytes expressed COX-2 and produced PGE(2) when exposed to LPS but not when acutely stimulated with A23187. Rat platelets, but not human platelets, also produced significant amounts of PGE(2) when acutely stimulated with A23187. These data show that when exposed to an inflammatory stimulus, rat whole blood produces increased levels of PGE(2) through induction of COX-2 in blood leukocytes. Rat blood, unlike human blood, may also produce copious amounts of PGE(2) via the actions of COX-1 enzyme constitutively present in platelets. These data may well explain why in rats COX-2-selective inhibitors have been reported not to produce the full anti-inflammatory effects associated with standard nonsteroid anti-inflammatory drugs.