Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma
E Ono, S Dutile, S Kazani, ME Wechsler… - American journal of …, 2014 - atsjournals.org
American journal of respiratory and critical care medicine, 2014•atsjournals.org
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 are decreased in severe asthma, yet mechanisms for defective LX
biosynthesis and a means to increase LXs in severe asthma remain to be established.
Objectives: To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are
linked to decreased LX biosynthesis in severe asthma. Methods: Aliquots of blood, sputum …
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.
Objectives: To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are
linked to decreased LX biosynthesis in severe asthma. Methods: Aliquots of blood, sputum …
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 are decreased in severe asthma, yet mechanisms for defective LX biosynthesis and a means to increase LXs in severe asthma remain to be established.
Objectives: To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are linked to decreased LX biosynthesis in severe asthma.
Methods: 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.
Measurements and Main Results: 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.
Conclusions: 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).
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