title: Epoxyeicosatrienoates are the dominant eicosanoids in human lungs upon microbial challenge.
abstract: Lipoxygenase, cyclo-oxygenase and cytochrome P450 (CYP) products of arachidonic acid (AA) are implicated in pulmonary vasoregulation. The CYP-mediated epoxyeicosatrienoates (EETs) have been described previously as the predominant eicosanoids in human lungs upon stimulation with the Ca(2+) ionophore A23187. In this study, we challenged perfused human lungs with two microbial agents: Escherichia coli haemolysin (ECH) and formyl-methionyl-leucyl-phenylalanine (fMLP). Both stimuli elicited pronounced generation of leukotrienes (LTs), hydroxyeicosatetraenoic acids (HETEs), prostanoids (PTs) and EETs/dihydroxyeicosatrienoic acids (DHETs), as assessed by liquid chromatography-mass spectrometry, paralleled by pulmonary artery pressor response and lung oedema formation. The maximum buffer concentrations of EETs/DHETs surpassed those of LTs plus HETEs and PTs by a factor of four (ECH) or three (AA/fMLP). Dual 5-lipoxygenase/cyclo-oxygenase inhibition caused pronounced reduction of AA/fMLP-induced LT/PT synthesis and oedema formation but only limited attenuation of pulmonary vasoconstriction, while inhibition of CYP epoxygenase clearly attenuated AA/fMLP-induced EET/DHET synthesis and vasoconstriction but not oedema formation, suggesting a major contribution of LTs/PTs to vascular leakage and of EETs/DHETs to pressor response. Consequently, generation of EETs/DHETs is greater than that of LTs plus HETEs and PTs in ex vivo perfused human lungs upon microbial challenge suggesting a substantial contribution of these mediators to inflammatory-infectious pulmonary injury.
authors.affiliation: Biochemical Laboratory, Dept of Internal Medicine, University of Gießen Lung Center, Justus Liebig University Gießen, Paul Meimberg Straße 5, D-35392 Gießen, Germany. ladislau.kiss@innere.med.uni-giessen.de
authors.forename: L
authors.initials: L
authors.lastname: Kiss
authors.forename: H
authors.initials: H
authors.lastname: Schütte
authors.forename: W
authors.initials: W
authors.lastname: Padberg
authors.forename: N
authors.initials: N
authors.lastname: Weissmann
authors.forename: K
authors.initials: K
authors.lastname: Mayer
authors.forename: T
authors.initials: T
authors.lastname: Gessler
authors.forename: R
authors.initials: R
authors.lastname: Voswinckel
authors.forename: W
authors.initials: W
authors.lastname: Seeger
authors.forename: F
authors.initials: F
authors.lastname: Grimminger
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000494:pharmacology*; D006460:Hemolysin Proteins / Q000494:pharmacology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D007975:Leukotriene B4 / Q000378:metabolism; D017999:Leukotriene E4 / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000378:metabolism* / Q000382:microbiology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D010477:Perfusion; D011453:Prostaglandins / Q000378:metabolism; D011652:Pulmonary Circulation / Q000502:physiology; D011817:Rabbits; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D015777:Eicosanoids; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; D006893:Hydroxyeicosatetraenoic Acids; D011453:Prostaglandins; D007975:Leukotriene B4; D016718:Arachidonic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D017999:Leukotriene E4; D003577:Cytochrome P-450 Enzyme System; D008084:Lipoxygenase; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid