Co-regulation between cyclo-oxygenase-2 and inducible nitric oxide synthase expression in the time-course of murine inflammation

Many in vitro studies have used cell cultures to focus on the relationships between cyclo-oxygenase-2. (COX-2) and inducible nitric oxide synthase (iN OS) isoforms. We have investigated the time-course of regulation and the ro le of COX-2 and iNOS in a model of experimental inflammation in mice, the a ir pouch injected with zymosan. This study demonstrates that there is an ea rly acute phase (4 h) mediated mainly by eicosanoids, with high levels of p rostaglandin E-2 (PGE(2)) produced by cyclooxygenase-1. In addition, in the later phase (from 12 h) there is a participation of nitric oxide (NO) and PGE(2) accompanied by co-induction of both iNOS and COX-2. These enzymes we re detected in migrating leukocytes as well as in macrophages lining the ai r pouch. Administration of NS398 or indomethacin inhibited PGE(2) levels an d COX activity, but also nitrite levels and iNOS activity, which was accomp anied by a reduction in iNOS expression. Aminoguanidine inhibited nitrite l evels and iNOS activity in addition to exerting inhibitory effects on the C OX pathway. Treatment of animals with dexamethasone reduced nitrite and PGE (2) concentrations in air pouch exudates, as well as iNOS and COX-2 express ion in migrating cells. Our results indicate that PGE(2) and NO may play in vivo mutual modulatory roles in the inflammatory response caused by zymosa n injection into the mouse air pouch, a suitable model to study drugs actin g on those pathways.