Abstract | 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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Authors | Emiko Ono, Stefanie Dutile, Shamsah Kazani, Michael E Wechsler, Jun Yang, Bruce D Hammock, David Nobuhiro Douda, Yacine Tabet, Rayan Khaddaj-Mallat, Marco Sirois, Chantal Sirois, Edmond Rizcallah, Eric Rousseau, Richard Martin, E Rand Sutherland, Mario Castro, Nizar N Jarjour, Elliot Israel, Bruce D Levy, National Heart, Lung, and Blood Institute's Asthma Clinical Research Network |
Journal | American journal of respiratory and critical care medicine
(Am J Respir Crit Care Med)
Vol. 190
Issue 8
Pg. 886-97
(Oct 15 2014)
ISSN: 1535-4970 [Electronic] United States |
PMID | 25162465
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Biomarkers
- Lipoxins
- Tumor Necrosis Factor-alpha
- lipoxin A4
- Epoxide Hydrolases
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Topics |
- Adult
- Asthma
(metabolism)
- Biomarkers
(metabolism)
- Bronchoalveolar Lavage Fluid
(chemistry)
- Case-Control Studies
- Epoxide Hydrolases
(antagonists & inhibitors, 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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