Lipoxin Generation Is Related to Soluble Epoxide Hydrolase Activity in Severe Asthma

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