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

Emiko Ono, Stefanie Dutile, Shamsah Kazani, Michael E. Wechsler, Jun Yang, Bruce D. Hammock, David N obuhiro 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

Research output: Contribution to journalArticle

36 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)886-897
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume190
Issue number8
DOIs
StatePublished - Oct 15 2014

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Keywords

  • asthma
  • inflammation
  • pro-resolving mediators
  • resolution

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ono, E., Dutile, S., Kazani, S., Wechsler, M. E., Yang, J., Hammock, B. D., Douda, D. N. O., Tabet, Y., Khaddaj-Mallat, R., Sirois, M., Sirois, C., Rizcallah, E., Rousseau, E., Martin, R., Sutherland, E. R., Castro, M., Jarjour, N. N., Israel, E., & Levy, B. D. (2014). Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma. American Journal of Respiratory and Critical Care Medicine, 190(8), 886-897. https://doi.org/10.1164/rccm.201403-0544OC