Prostaglandin E2 mediates lipopolysaccharide-induced macrophage procoagulant activity by a cyclic adenosine monophosphate-dependent pathway
Williams, J.G.; Garcia, I.; Maier, R.V.
Surgery 114(2): 314-323
1993
ISSN/ISBN: 0039-6060 PMID: 7688154 Document Number: 415838
Background. Multiple organ failure syndrome (MOFS) and adult respiratory distress syndrome (ARDS) continue to be significant clinical problems. 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 (PCA) after exposure to endotoxin. One potential method to ameliorate organ dysfunction in ARDS and MOFS is to prevent macrophage activation of the coagulation cascade, Because inhibitors of arachidonic acid metabolism attenuate inflammatory lung injury, we investigated the role of eicosanoids in endotoxin-induced alveolar macrophage PCA. Methods. Rabbit alveolar macrophages were incubated with selective inhibitors of arachidonic acid metabolism. PCA was determined in cell lysates. PCA was also assessed in cultures treated with cyclooxygenase inhibitor that had exogenous prostaglandin E-2 (PGE-2) added. Intracellular cyclic adenosine monophosphate (cAMP) was examined after treatment with lipopolysaccharide, ibuprofen, PGE-2, and forskolin. Results. Ibuprofen significantly reduces lipopolysaccharide-stimulated PCA by alveolar macrophages. 5-Lipoxygenase and thromboxane synthetase inhibitors had no effect on PCA. Inhibition of PCA by ibuprofen is reversed by adding exogenous PGE-2. Decreased intracellular cAMP is associated with attenuated lipopolysaccharide-stimulated PCA elaboration. Conclusions. Endotoxin-stimulated alveolar macrophage PCA is prostanoid dependent, with cAMP acting as a second messenger. Although expression of PCA is prostanoid-cAMP dependent, neither prostanoids nor agents that directly increase cAMP are sufficient to elicit PCA in the absence of lipopolysaccharide.