title: Phospholipid Ozonation Products Activate the 5-Lipoxygenase Pathway in Macrophages.
abstract: Ozone is a highly reactive environmental toxicant that can react with the double bonds of lipids in pulmonary surfactant. This study was undertaken to investigate the proinflammatory properties of the major lipid-ozone product in pulmonary surfactant, 1-palmitoyl-2-(9'-oxo-nonanoyl)-glycerophosphocholine (16:0/9al-PC), with respect to eicosanoid production. A dose-dependent increase in the formation of 5-lipoxygenase (5-LO) products was observed in murine resident peritoneal macrophages (RPM) and alveolar macrophages (AM) upon treatment with 16:0/9al-PC. In contrast, the production of cyclooxygenase (COX) derived eicosanoids did not change from basal levels in the presence of 16:0/9al-PC. When 16:0/9al-PC and the TLR2 ligand, zymosan, were added to RPM or AM, an enhancement of 5-LO product formation along with a concomitant decrease in COX product formation was observed. Neither intracellular calcium levels nor arachidonic acid release was influenced by the addition of 16:0/9al-PC to RPM. Results from mitogen-activated protein kinase (MAPK) inhibitor studies and direct measurement of phosphorylation of MAPKs revealed that 16:0/9al-PC activates the p38 MAPK pathway in RPM, which results in the activation of 5-LO. Our results indicate that 16:0/9al-PC has a profound effect on the eicosanoid pathway, which may have implications in inflammatory pulmonary disease states where eicosanoids have been shown to play a role.
authors.affiliation: Department of Pharmacology, University of Colorado Denver , 12801 E. 17th Avenue, Mail Stop 8303, Aurora, Colorado 80045, United States.
authors.forename: Karin A
authors.initials: KA
authors.lastname: Zemski Berry
authors.affiliation: Department of Pharmacology, University of Colorado Denver , 12801 E. 17th Avenue, Mail Stop 8303, Aurora, Colorado 80045, United States.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D005260:Female; D016676:Macrophages, Alveolar / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010126:Ozone / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*
chemical_list: D010743:Phospholipids; D010126:Ozone; D001094:Arachidonate 5-Lipoxygenase