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

34 Citations (Scopus)

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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Lipoxins
Epoxide Hydrolases
Asthma
Leukocytes
Sputum
tert-Butylhydroperoxide
8-epi-prostaglandin F2alpha
Blood Platelets
Bronchoalveolar Lavage Fluid
Oxidative Stress
lipoxin A4
Platelet Activating Factor
Arachidonic Acid
Flow Cytometry
Tumor Necrosis Factor-alpha
Clinical Trials
Cytokines

Keywords

  • asthma
  • inflammation
  • pro-resolving mediators
  • resolution

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma. / Ono, Emiko; Dutile, Stefanie; Kazani, Shamsah; Wechsler, Michael E.; Yang, Jun; Hammock, Bruce D.; Douda, David N obuhiro; Tabet, Yacine; Khaddaj-Mallat, Rayan; Sirois, Marco; Sirois, Chantal; Rizcallah, Edmond; Rousseau, Eric; Martin, Richard; Sutherland, E. Rand; Castro, Mario; Jarjour, Nizar N.; Israel, Elliot; Levy, Bruce D.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 190, No. 8, 15.10.2014, p. 886-897.

Research output: Contribution to journalArticle

Ono, E, Dutile, S, Kazani, S, Wechsler, ME, Yang, J, Hammock, BD, Douda, DNO, Tabet, Y, Khaddaj-Mallat, R, Sirois, M, Sirois, C, Rizcallah, E, Rousseau, E, Martin, R, Sutherland, ER, Castro, M, Jarjour, NN, Israel, E & Levy, BD 2014, 'Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma', American Journal of Respiratory and Critical Care Medicine, vol. 190, no. 8, pp. 886-897. https://doi.org/10.1164/rccm.201403-0544OC
Ono, Emiko ; Dutile, Stefanie ; Kazani, Shamsah ; Wechsler, Michael E. ; Yang, Jun ; Hammock, Bruce D. ; Douda, David N obuhiro ; Tabet, Yacine ; Khaddaj-Mallat, Rayan ; Sirois, Marco ; Sirois, Chantal ; Rizcallah, Edmond ; Rousseau, Eric ; Martin, Richard ; Sutherland, E. Rand ; Castro, Mario ; Jarjour, Nizar N. ; Israel, Elliot ; Levy, Bruce D. / Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma. In: American Journal of Respiratory and Critical Care Medicine. 2014 ; Vol. 190, No. 8. pp. 886-897.
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T1 - Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma

AU - Ono, Emiko

AU - Dutile, Stefanie

AU - Kazani, Shamsah

AU - Wechsler, Michael E.

AU - Yang, Jun

AU - Hammock, Bruce D.

AU - Douda, David N obuhiro

AU - Tabet, Yacine

AU - Khaddaj-Mallat, Rayan

AU - Sirois, Marco

AU - Sirois, Chantal

AU - Rizcallah, Edmond

AU - Rousseau, Eric

AU - Martin, Richard

AU - Sutherland, E. Rand

AU - Castro, Mario

AU - Jarjour, Nizar N.

AU - Israel, Elliot

AU - Levy, Bruce D.

PY - 2014/10/15

Y1 - 2014/10/15

N2 - 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).

AB - 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).

KW - asthma

KW - inflammation

KW - pro-resolving mediators

KW - resolution

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