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Epoxyeicosatrienoates Are the Dominant Eicosanoids in Human Lungs Upon Microbial Challenge

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Epoxyeicosatrienoates Are the Dominant Eicosanoids in Human Lungs Upon Microbial Challenge Eur Respir J 2010; 36: 1088–1098 DOI: 10.1183/09031936.00000309 CopyrightßERS 2010 Epoxyeicosatrienoates are the dominant eicosanoids in human lungs upon microbial challenge L. Kiss*, H. Schu¨tte#, W. Padberg", N. Weissmann+, K. Mayer*, T. Gessler*, R. Voswinckel*, W. Seeger* and F. Grimminger* ABSTRACT: Lipoxygenase, cyclo-oxygenase and cytochrome P450 (CYP) products of AFFILIATIONS arachidonic acid (AA) are implicated in pulmonary vasoregulation. The CYP-mediated *University of Gießen Lung Center (UGLC)/Dept of Internal Medicine, epoxyeicosatrienoates (EETs) have been described previously as the predominant eicosanoids "Dept of Surgery, 2+ in human lungs upon stimulation with the Ca ionophore A23187. In this study, we challenged +UGLC/Excellence Cluster perfused human lungs with two microbial agents: Escherichia coli haemolysin (ECH) and formyl- Cardiopulmonary System (ECCPS), methionyl-leucyl-phenylalanine (fMLP). Justus Liebig University, Gießen, and #Dept of Internal Medicine/Infectious Both stimuli elicited pronounced generation of leukotrienes (LTs), hydroxyeicosatetraenoic and Respiratory Diseases, Charite´- acids (HETEs), prostanoids (PTs) and EETs/dihydroxyeicosatrienoic acids (DHETs), as assessed Universita¨tsmedizin Berlin, Berlin, by liquid chromatography–mass spectrometry, paralleled by pulmonary artery pressor response Germany. and lung oedema formation. The maximum buffer concentrations of EETs/DHETs surpassed those CORRESPONDENCE of LTs plus HETEs and PTs by a factor of four (ECH) or three (AA/fMLP). Dual 5-lipoxygenase/ L. Kiss cyclo-oxygenase inhibition caused pronounced reduction of AA/fMLP-induced LT/PT synthesis Biochemical Laboratory, University of and oedema formation but only limited attenuation of pulmonary vasoconstriction, while inhibition Gießen Lung Center (UGLC), Dept of of CYP epoxygenase clearly attenuated AA/fMLP-induced EET/DHET synthesis and vasoconstric- Internal Medicine Justus Liebig University Gießen tion but not oedema formation, suggesting a major contribution of LTs/PTs to vascular leakage Paul Meimberg Straße 5 and of EETs/DHETs to pressor response. D-35392 Gießen Consequently, generation of EETs/DHETs is greater than that of LTs plus HETEs and PTs in ex Germany vivo perfused human lungs upon microbial challenge suggesting a substantial contribution of E-mail: ladislau.kiss@ innere.med.uni-giessen.de these mediators to inflammatory–infectious pulmonary injury. Received: KEYWORDS: Cyclo-oxygenase, cytochrome P450, eicosanoids, human lung, lipoxygenase, Jan 02 2009 soluble epoxide hydrolase Accepted after revision: March 28 2010 First published online: April 08 2010 he lung vasculature is known to be a rich LTs are implicated in a variety of vascular source of lipid mediator biosynthesis from abnormalities occurring under conditions of lung T arachidonic acid (AA) via the enzymatic inflammation, such as pre- and post-capillary pathways of the AA cascade: lipoxygenase (LOX), vasoconstriction and vascular leakage (cysteinyl- cytochrome P450 (CYP), soluble epoxide hydro- LTs) as well as leukocyte chemotaxis and activa- lase (sEH) and cyclo-oxygenase (COX) [1–12]. The tion (LTB4), while HETEs may additionally affect different eicosanoids encompass the LOX- leukocyte kinetics and lung fluid homeostasis [5, mediated leukotrienes (LTs) and lipoxins (LXs), 6, 13]. Studies with polymorphonuclear neutro- the CYP-mediated epoxyeicosatrienoic acids phils (PMNs) in vitro and in buffer-perfused (epoxyeicosatrienoates; EETs), the sEH-mediated rabbit lungs, which are known to harbour large dihydroxyeicosatrienoic acids (DHETs), the COX- quantities of resident neutrophils, monocytes and mediated prostanoids (PTs) (prostaglandins (PGs) lymphocytes even after extensive rinsing [14, 15], and thromboxanes (TXs)) and the cis–trans con- demonstrated high yields of LT and HETE jugated hydroxyeicosatetraenoic acids (HETEs) formation upon simultaneous application of free mediated by LOX, CYP or COX (overview in AA and inflammatory ligands, such as formyl- fig. 1). They display a broad array of biological methionyl-leucyl-phenylalanine (fMLP) or the functions, ranging from proinflammatory and bacterial toxin Escherichia coli haemolysin (ECH) European Respiratory Journal vasoconstrictive, to anti-inflammatory and vaso- [8, 16, 17]. This abundant mediator generation is a Print ISSN 0903-1936 dilatory properties [1, 4, 5, 11]. result of substantial AA liberation at sites of Online ISSN 1399-3003 1088 VOLUME 36 NUMBER 5 EUROPEAN RESPIRATORY JOURNAL L. KISS ET AL. RESPIRATORY INFECTIONS AND LUNG INJURY 9865 enhanced production of prostanoids [11, 24–26]. In contrast to COOH the systemic cardiovascular compartment, where EETs/ DHETs were proposed and discussed over a decade ago as 11 12 14 15 chemical correlates of the vasodilatative endothelium-derived hyperpolarising factor (EDHF) [27–30], the role of these CYP/ AA sEH-mediated autacoids in the pulmonary circulation is poorly investigated. Interestingly, first reports describe them as both LOX CYP COX vasoconstrictors and vasodilators [11, 24] and, as previously described by our group [10], inflammatory challenge of human lungs with the nonphysiological Ca2+ ionophore A23187 evoked the enhanced release of a broad array of eicosanoids, LTs EETs PTs with the CYP-mediated EETs being by far the predominant HETEs HETEs HETEs mediators, paralleled by an increase in pulmonary arterial LXs pressure (DPpa) and lung weight gain (DW). CYPω sEH In the present study, we extended this approach by asking whether the challenge of human lungs with pathophysio- logically relevant microbial stimuli per se, such as the protein- ω -ox-LTB4 DHETs aceous transmembrane pore-forming exotoxin ECH and the inflammatory and chemotactic bacterial receptor-operated FIGURE 1. The main pathways of the arachindonic acid (AA) cascade. LOX: tripeptide fMLP, administered in the presence of exogenous lipoxygenase; LT: leukotrienes (LTB4,LTC4, LTD4 and LTE4); HETE: hydroxyeico- AA availability might elicit a similar eicosanoid profile as satetraenoic acid (15-HETE, 11-HETE, 8-HETE, 12-HETE, 9-HETE and 5-HETE); LX: A23187 and whether such metabolic responses are linked with lipoxin (LXA4 and LXB4); CYPv: cytochrome P450 v-oxygenase; v-ox-LTB4: v- vasoconstrictor response and oedema formation in the human oxygenase-mediated LTB4 metabolites (20-HO-LTB4, 20-COOH-LTB4); CYP: pulmonary compartment. Studies were performed with iso- cytochrome P450; EETs: epoxyeicosatrienoic acids (14,15-EET, 11,12-EET, 8,9- lated, perfused and ventilated intact human lungs, employing EET and 5,6-EET); sEH: soluble epoxide hydrolase; DHET: dihydroxyeicosatrienoic a combined technique of multistep solid-phase extraction (SPE) acid (14,15-DHET, 11,12-DHET, 8,9-DHET, 5,6-DHET and 5,6-DHET d-lactone); of buffer fluid followed by isocratic capillary liquid chromato- COX: cyclo-oxygenase; PT: prostanoids (prostaglandins (PGI2, 6-keto-PGF1a, graphy (CapLC) with dual online photodiode array detection PGE2, PGD2 and PGF2a) and thromboxanes (TXA2 and TXB2)). (PDAD) and electrospray ionisation (ESI) tandem mass- spectrometric (MS/MS) detection for simultaneous assessment inflammatory events and leukocyte–endothelial cooperation in of all LOX-, COX-, CYP- and sEH-mediated representatives of LT synthesis, including 1) a transfer of the unstable LT the AA cascade [31]. Comprehensive eicosanoid profiling with this CapLC-PDAD-ESI-MS/MS method revealed the release of intermediate LTA4 from PMN feeder cells to acceptor endothelial cells (ECs) with subsequent employment of the virtually all the main representatives of the AA cascade in enzymatic equipment of the latter for transformation into LTs, response to both microbial challenges, with the absolute and 2) release of free AA from ECs with uptake and processing predominance (by a factor of three to four) of the CYP/sEH- of this precursor by the adjacent PMNs [3, 16–21]. mediated EETs/DHETs over the other lipid mediators. This mediator liberation profile was paralleled by a pulmonary The ubiquitous, as yet poorly investigated, six HETE regio- arterial vasoconstrictor response, to which the CYP epoxygen- isomers display varying biological activities, ranging from ase pathway may particularly contribute, and DW, which may anti-inflammatory (15-HETE) to proinflammatory (5-HETE) be mainly a result of LOX and COX activity. properties, and including chemotaxis (5-HETE, 11-HETE and 12-HETE) and regulation of the enzymatic pathways of the AA MATERIALS AND METHODS cascade [1, 5, 13, 22, 23]. Materials The physiological properties of the well-investigated PTs reach AA, 20-carboxy-LTB4, 20-hydroxy-LTB4, LTC4, LTD4, LTE4, from vasoconstrictive (TXA2, PGF2a) to vasodilatative (PGI2, PGB1, 6t-LTB4, 6t,12e-LTB4, LTB4, LXA4, LXB4, 5S,6R-DiHETE, PGD2 and PGE2) functions [1, 5]. TXA2 and PGI2 represent a 5S,6S-DiHETE, and 15-, 11-, 8-, 12-, 9- and 5-HETE, were classical example of an antagonistic pair of mediators: purchased from Biomol GmbH (Hamburg, Germany). 14,15-, vasocontriction and the resulting mismatch between pulmon- 11,12-, 8,9-, 5,6-EET, and 14,15-, 11,12-, 8,9-, 5,6-DHET and 5,6- DHET d-lactone were supplied by Biomol and by Cayman ary perfusion and ventilation provoked by TXA2 is counter- Chemical Company (Ann Arbor, MI, USA). 6-keto-PGF a, acted by prostacyclin (PGI2). Likewise, the adhesive and 1 PGD , PGE , PGF a, TXB and stearidonic acid (SDA) were aggregatory actions of TXA2 are counteracted by the anti- 2 2 2 2 obtained from Cayman. fMLP, butylated hydroxytoluene adhesive and antiaggregatory
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