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Am J Respir Crit Care Med. 2014 Oct 15;190(8):886-97. doi: 10.1164/rccm.201403-0544OC.

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

Author information

1
1 Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

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).

KEYWORDS:

asthma; inflammation; pro-resolving mediators; resolution

PMID:
25162465
PMCID:
PMC4299578
DOI:
10.1164/rccm.201403-0544OC
[Indexed for MEDLINE]
Free PMC Article

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