title: E. coli hemolysin-induced lipid mediator metabolism in alveolar macrophages: impact of eicosapentaenoic acid.
abstract: Escherichia coli hemolysin (HlyA) is a prototype of a large family of pore-forming proteinaceous exotoxins that have been implicated in the pathogenetic sequelae of severe infection and sepsis, including development of acute lung injury. In the present study in rabbit alveolar macrophages (AMs), subcytolytic concentrations of purified HlyA evoked rapid synthesis of platelet-activating factor, with quantities approaching those in response to maximum calcium ionophore challenge. In parallel, large quantities of leukotriene (LT) B(4) and 5-, 8-, 9-, 12-, and 15-hydroxyeicosatetraenoic acid (HETE) were liberated from HlyA-exposed AMs depending on exogenous arachidonic acid (AA) supply. Coadministration of eicosapentaenoic acid (EPA) dose dependently suppressed generation of the proinflammatory lipoxygenase products LTB(4) and 5-, 8-, 9-, and 12-HETE in parallel with the appearance of the corresponding EPA-derived metabolites LTB(5) and 5-, 8-, 9-, and 12-hydroxyeicosapentaenoic acid (HEPE). At equimolar concentrations, EPA turned out to be the preferred substrate over AA for these AM lipoxygenase pathways, with the sum of LTB(5) and 5-, 8-, 9-, and 12-HEPE surpassing the sum of LTB(4) and 5-, 8-, 9-, and 12-HETE by >80-fold. In contrast, coadminstration of EPA did not significantly reduce HlyA-elicited generation of the anti-inflammatory AA lipoxygenase product 15-HETE. We conclude that AMs are sensitive target cells for HlyA attack, resulting in marked proinflammatory lipid mediator synthesis. In the presence of EPA, lipoxygenase product formation is shifted from a pro- to an anti-inflammatory profile.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University, 35385 Giessen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Rose
authors.forename: L
authors.initials: L
authors.lastname: Kiss
authors.forename: F
authors.initials: F
authors.lastname: Grimminger
authors.forename: K
authors.initials: K
authors.lastname: Mayer
authors.forename: U
authors.initials: U
authors.lastname: Grandel
authors.forename: W
authors.initials: W
authors.lastname: Seeger
authors.forename: E
authors.initials: E
authors.lastname: Bieniek
authors.forename: U
authors.initials: U
authors.lastname: Sibelius
mesh_terms: D000818:Animals; D015777:Eicosanoids / Q000096:biosynthesis; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D004926:Escherichia coli / Q000378:metabolism*; D006460:Hemolysin Proteins / Q000378:metabolism / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007975:Leukotriene B4 / Q000378:metabolism; D050356:Lipid Metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000378:metabolism; D011817:Rabbits
chemical_list: D015777:Eicosanoids; D006460:Hemolysin Proteins; D006893:Hydroxyeicosatetraenoic Acids; D018836:Inflammation Mediators; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D007975:Leukotriene B4; D015118:Eicosapentaenoic Acid