Asthma and lower airway disease
Exhaled breath condensate eicosanoid levels associate with asthma and its severity

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Background

The relationship between anti-inflammatory lipoxins and proinflammatory leukotrienes might be important in the pathobiology and severity of asthma.

Objective

We sought to investigate whether exhaled breath condensate (EBC) lipoxin and leukotriene measurements can noninvasively characterize the asthmatic diathesis and its severity.

Methods

We measured lipoxin A4 (LXA4) and leukotriene B4 (LTB4) levels in EBC collected from patients with asthma of different severities and from healthy control subjects.

Results

EBC LXA4 and LTB4 levels are increased in asthmatic patients compared with those seen in healthy control subjects (LXA4: 31.40 vs 2.41 pg/mL EBC, respectively [P < .001]; LTB4: 45.62 vs 3.82 pg/mL EBC, respectively [P < .001]). Although levels of both eicosanoids are increased in asthmatic patients, the LXA4/LTB4 ratio decreases with increasing asthma severity. It is 41% lower in patients with severe versus moderate asthma (0.52 vs 0.88, P = .034). EBC LXA4 levels correlate with the degree of airflow obstruction measured by using FEV1 (r = 0.28, P = .018). An LXA4 cutoff value of 7 pg/mL EBC provides 90% sensitivity and 92% specificity for the diagnosis of asthma (area under the curve, 0.96; P < .001). An LTB4 cutoff value of 11 pg/mL EBC provides 100% sensitivity and 100% specificity for the diagnosis of asthma (area under the curve, 1; P < .001).

Conclusions

Proresolving and proinflammatory eicosanoids are generated in the airways of all asthmatic patients. The proportion of proresolving compounds decreases with asthma severity. These findings support the role for EBC eicosanoid measurements in the noninvasive diagnosis of asthma and suggest that proresolving eicosanoid pathways are dysregulated in patients with severe asthma.

Section snippets

Participants

All participants provided written informed consent that was approved by the institutional review board. We recruited adults with mild intermittent, moderate, and severe asthma to participate in a phenotypic characterization study as part of the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. Severe asthma was defined per the criteria developed by the American Thoracic Society Workshop on Refractory Asthma.22 Patients with moderate asthma were required to be taking

Participants' characteristics

Table I, Table II describe the demographic and phenotypic characteristics of the participants. Patients with severe asthma were the oldest among the 4 groups. Groups were similar with respect to the distribution of sex, race, and ethnicity. As expected, patients with severe asthma received much higher doses of ICSs and had lower lung function. There were no other significant differences between the patients with moderate and those with severe asthma, similar to what has been seen in the entire

Discussion

Using direct in vivo measurements from the airways, we demonstrate that the lipoxin and leukotriene pathways are upregulated in patients with asthma of all severities. Our data also provide in vivo confirmation that relative underproduction of lipoxins occurs with increasing asthma severity. Lastly, our data suggest that noninvasively obtained EBC measurements of representative eicosanoids from these pathways distinguish asthmatic from nonasthmatic patients with high sensitivity and

References (39)

  • C. Mondino et al.

    Effects of inhaled corticosteroids on exhaled leukotrienes and prostanoids in asthmatic children

    J Allergy Clin Immunol

    (2004)
  • P.E. Silkoff et al.

    Dose-response relationship and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients

    Chest

    (2001)
  • J. Yang et al.

    Metabolomic profiling of regulatory lipid mediators in sputum from adult cystic fibrosis patients

    Free Radic Biol Med

    (2012)
  • R. Chiron et al.

    Lipoxin A(4) and interleukin-8 levels in cystic fibrosis sputum after antibiotherapy

    J Cyst Fibros

    (2008)
  • J.M. Drazen et al.

    Treatment of asthma with drugs modifying the leukotriene pathway

    N Engl J Med

    (1999)
  • C.N. Serhan et al.

    Novel pathways and endogenous mediators in anti-inflammation and resolution

    Chem Immunol Allergy

    (2003)
  • B.D. Levy et al.

    Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A(4)

    Nat Med

    (2002)
  • C. Bandeira-Melo et al.

    Inhibition of allergen-induced eosinophil migration by lipoxin (LX)A4 and aspirin-triggered 15-epi-LXA4

    Adv Exp Med Biol

    (2002)
  • K.F. Badr et al.

    Lipoxin A4 antagonizes cellular and in vivo actions of leukotriene D4 in rat glomerular mesangial cells: evidence for competition at a common receptor

    Proc Natl Acad Sci U S A

    (1989)
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    Supported by NIH/NLHBI grants HL069349, HL107166, and HL109172; NIH/NIAID grant AI068084; and NIH/NCRR grants RR022292, RR025757, and RR025758.

    Disclosure of potential conflict of interest: S. Kazani has received research and travel support from the National Institutes of Health (National Heart Lung and Blood Institute's Severe Asthma Research Program and Asthma Clinical Research Network) and the American Lung Institute. The work was conducted with the support of a KL2 Medical Research Investigator Training (MeRIT) award from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award 8KL2TR000168-05). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health. M. E. Wechsler has consultant arrangements with GlaxoSmithKline, Novartis, Cephalon/TEVA, Sepracor/SUNOVION, Schering-Plough, NKT Therapeutics, Asthmatx/BSCI, Genzyme, MapPharma, Genentech, Boehringer Ingelheim, Merck, and Cytos and has received payment for lectures from Merck. B. D. Levy has received research support from the National Institutes of Health; has consultant arrangements with Novartis, Eisai, and Fresenius; and is coinventor on patents issued on lipoxins in airway diseases that were outlicensed by Brigham and Women's Hospital for clinical development. E. Israel has consultant arrangements with Abbott, Amgen, Cowen & Co, Infinity Pharmaceuticals, MedImmune (now AstraZeneca), Merck, newMentor, NKT Therapeutics, Ono Pharmaceuticals, Regeneron Pharmaceuticals, Schering Plough, TEVA Specialty Pharmaceuticals, Gilead Sciences, Johnson & Johnson, and Agenzia Italiana del Farmico; has provided expert testimony for Campbell, Campbell, Edwards & Conroy, Diedrich & Donohue, Ficksman & Conley, Ryan Ryan Deluca LLP, and Sullway & Hollis; has received grants from Aerovance, Amgen, i3 Research (Biota), Genentech, MedImmune, and Novartis; has received payment for lectures from Merck, the Spanish Society of Allergy & Immunology (SEAIC Congress-Madrid), Western Society of Allergy, Asthma & Immunology (WSAAI-Maui), and the World Allergy Congress (WAC-Cancun and WAC-India); and has received royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest.

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