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Title: Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma.

Authors: Ono, Emiko; Dutile, Stefanie; Kazani, Shamsah; Wechsler, Michael E; Yang, Jun; Hammock, Bruce D; Douda, David Nobuhiro; Tabet, Yacine; Khaddaj-Mallat, Rayan; Sirois, Marco; Sirois, Chantal; Rizcallah, Edmond; Rousseau, Eric; Martin, Richard; Sutherland, E Rand; Castro, Mario; Jarjour, Nizar N; Israel, Elliot; Levy, Bruce D; National Heart, Lung, and Blood Institute's Asthma Clinical Research Network

Published In Am J Respir Crit Care Med, (2014 Oct 15)

Abstract: Severe asthma is characterized by airway inflammatory responses associated with aberrant metabolism of arachidonic acid. Lipoxins (LX) are arachidonate-derived pro-resolving mediators that are decreased in severe asthma, yet mechanisms for defective LX biosynthesis and a means to increase LXs in severe asthma remain to be established.To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are linked to decreased LX biosynthesis in severe asthma.Aliquots of blood, sputum, and bronchoalveolar lavage fluid were obtained from asthma subjects for mediator determination. Select samples were exposed to t-butyl-hydroperoxide or sEH inhibitor (sEHI) before activation. Peripheral blood leukocyte-platelet aggregates were monitored by flow cytometry, and bronchial contraction was determined with cytokine-treated human lung sections.8-Isoprostane levels in sputum supernatants were inversely related to LXA4 in severe asthma (r = -0.55; P = 0.03) and t-butyl-hydroperoxide decreased LXA4 and 15-epi-LXA4 biosynthesis by peripheral blood leukocytes. LXA4 and 15-epi-LXA4 levels were inversely related to sEH activity in sputum supernatants and sEHIs significantly increased 14,15-epoxy-eicosatrienoic acid and 15-epi-LXA4 generation by severe asthma whole blood and bronchoalveolar lavage fluid cells. The abundance of peripheral blood leukocyte-platelet aggregates was related to asthma severity. In a concentration-dependent manner, LXs significantly inhibited platelet-activating factor-induced increases in leukocyte-platelet aggregates (70.8% inhibition [LXA4 100 nM], 78.3% inhibition [15-epi-LXA4 100 nM]) and 15-epi-LXA4 markedly inhibited tumor necrosis factor-α-induced increases in bronchial contraction.LX levels were decreased by oxidative stress and sEH activity. Inhibitors of sEH increased LXs that mediated antiphlogistic actions, suggesting a new therapeutic approach for severe asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 00595114).

PubMed ID: 25162465 Exiting the NIEHS site

MeSH Terms: Adult; Asthma/metabolism*; Biomarkers/metabolism; Bronchoalveolar Lavage Fluid/chemistry; Case-Control Studies; Epoxide Hydrolases/antagonists & inhibitors; Epoxide Hydrolases/metabolism*; Female; Flow Cytometry; Humans; Lipoxins/metabolism*; Male; Middle Aged; Oxidative Stress*; Severity of Illness Index; Sputum/chemistry; Tumor Necrosis Factor-alpha/metabolism

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