PROSTAGLANDIN-E(2) MEDIATES LIPOPOLYSACCHARIDE-INDUCED MACROPHAGE PROCOAGULANT ACTIVITY BY A CYCLIC ADENOSINE-MONOPHOSPHATE DEPENDENT PATHWAY

Background. Multiple organ failure syndrome (MOFS) and adult respirato ry distress syndrome (ARDS) continue to be significant clinical proble ms. Microvascular thrombosis and intraalveolar fibrin deposition play an integral role in the pathogenesis of MOFS and ARDS. The macrophage participates in these processes by expressing procoagulant activity (P CA) after exposure to endotoxin. One potential method to ameliorate or gan dysfunction in ARDS and MOFS is to prevent macrophage activation o f the coagulation cascade. Because inhibitors of arachidonic acid meta bolism attenuate inflammatory lung injury, we investigated the role of eicosanoids in endotoxin-induced alveolar macrophage PCA. Methods. Ra bbit alveolar macrophages were incubated with selective inhibitors of arachidonic acid metabolism. PCA was determined in cell lysates. PCA w as also assessed in cultures treated with cyclooxygenase inhibitor tha t had exogenous prostaglandin E2 (PGE2) added. Intracellular cyclic ad enosine monophosphate (cAMP) was examined after treatment with lipopol ysaccharide, ibuprofen, PGE2, and forskolin. Results. Ibuprofen signif icantly reduces lipopolysaccharide-stimulated PCA by alveolar macropha ges. 5-Lipoxygenase and thromboxane synthetase inhibitors had no effec t on PCA. Inhibition of PCA by ibuprofen is reversed by adding exogeno us PGE2. Decreased intracellular cAMP is associated with attenuated li popolysaccharide-stimulated PCA elaboration. Conclusions. Endotoxin-st imulated alveolar macrophage PCA is prostanoid dependent, with cAMP ac ting as a second messenger. Although expression of PCA is prostanoid-c AMP dependent, neither prostanoids nor agents that directly increase c AMP are sufficient to elicit PCA in the absence of lipopolysaccharide.