title: Prostaglandin E2 mediates lipopolysaccharide-induced macrophage procoagulant activity by a cyclic adenosine monophosphate-dependent pathway.
abstract: 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 E2 (PGE2) added. Intracellular cyclic adenosine monophosphate (cAMP) was examined after treatment with lipopolysaccharide, ibuprofen, PGE2, 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 PGE2. 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.
authors.affiliation: Department of Surgery, University of Texas Southwestern Medical Center, Dallas 75235-9031.
authors.forename: J G
authors.initials: JG
authors.lastname: Williams
authors.forename: I
authors.initials: I
authors.lastname: Garcia
authors.forename: R V
authors.initials: RV
authors.lastname: Maier
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D001779:Blood Coagulation Factors / Q000096:biosynthesis*; D000242:Cyclic AMP / Q000502:physiology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology*; D007052:Ibuprofen / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D002722:Chlorobenzenes
chemical_list: D015056:1-Methyl-3-isobutylxanthine; D000262:Adenylyl Cyclases; D001779:Blood Coagulation Factors; D000242:Cyclic AMP; D015232:Dinoprostone; D007052:Ibuprofen; D007093:Imidazoles; D007211:Indoles; D008070:Lipopolysaccharides; C045072:macrophage procoagulant activity; C060893:MK-886; D002722:Chlorobenzenes; C029899:imidazole