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Author Notes:

Rabindra Tirouvanziam, PhD, Emory Children’s Center, 2015 Uppergate Dr NE, Rm 344, Atlanta, GA 30322, USA, Ph: +1 404 712 7684; tirouvanziam@emory.edu

Experimental conception and design: RT, HMJ, BJS, JDC. Performed experiments: JDC, HH, CM, MBK, MV. Interpreted results and provided critical support: JDC, HH, CM, MBK, HKL, BJS, HAWMT, AJT, LP, LG, KU, YMG, HMJ, DPJ, RT. Prepared manuscript: JDC. Reviewed or edited and approved manuscript: All authors.

We thank the patients and their families for consenting to participate in this study. We acknowledge research coordinators E. Nieuwhof, E. van der Wiel and B. Manai (Erasmus MC-Sophia, Rotterdam, The Netherlands) for their support in recruiting patients. We thank M.W.H. Pijnenburg, J.C. de Jongste, L. Duijts, S. Kloosterman and I.M. de Kleer (Erasmus MC-Sophia, Rotterdam, The Netherlands) for performing bronchoscopies. We thank M. Kemner (Erasmus MC-Sophia, Rotterdam, The Netherlands) for her guidance with PRAGMA-CF scoring. We thank Nina Dickerhof (University of Otago, Christchurch, New Zealand) for insightful technical discussions about the MPO assay method.

Subjects:

Research Funding:

Supported by NHLBI F32 HL132493 (J.D. Chandler); Emory Children’s CF and Airways Disease Research Center Startup Fund (J.D. Chandler and M.B. Kilgore); CFF P30 MCCART15R0 (C. Margaroli); NHLBI R01 HL126603 and Common Fund for Metabolomics Supplement HL126603-02S1 (R. Tirouvanziam, A.J. Taurone, L. Peng, H. Horati, H.M. Janssens, B.J. Scholte and M. Veltman); Dutch Cystic Fibrosis Foundation (NCFS) grant HIT-CF 1 and 2 (H. Horati, M. Veltman, B.J. Scholte, H.A.W.M. Tiddens and H.M. Janssens); ERARE INSTINCT (M. Veltman and B.J. Scholte); and P30 ES019776, S10 OD018006 and R01 ES023485 (H.K. Liu, K. Uppal, Y-M. Go and D.P. Jones).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Respiratory System
  • ABSOLUTE RATE CONSTANTS
  • GLUTATHIONE
  • INFLAMMATION
  • CHILDREN
  • OXIDANTS
  • PROTEIN
  • THERMODYNAMICS
  • BRONCHIECTASIS
  • METABOLOMICS
  • THIOCYANATE

Myeloperoxidase oxidation of methionine associates with early cystic fibrosis lung disease

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Journal Title:

EUROPEAN RESPIRATORY JOURNAL

Volume:

Volume 52, Number 4

Publisher:

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Cystic fibrosis (CF) lung disease progressively worsens from infancy to adulthood. Disease-driven changes in early CF airway fluid metabolites may identify therapeutic targets to curb progression. CF patients aged 12–38 months (n=24; three out of 24 later denoted as CF screen positive, inconclusive diagnosis) received chest computed tomography scans, scored by the Perth–Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) method to quantify total lung disease (PRAGMA-%Dis) and components such as bronchiectasis (PRAGMA-%Bx). Small molecules in bronchoalveolar lavage fluid (BALF) were measured with high-resolution accurate-mass metabolomics. Myeloperoxidase (MPO) was quantified by ELISA and activity assays. Increased PRAGMA-%Dis was driven by bronchiectasis and correlated with airway neutrophils. PRAGMA-%Dis correlated with 104 metabolomic features (p<0.05, q<0.25). The most significant annotated feature was methionine sulfoxide (MetO), a product of methionine oxidation by MPO-derived oxidants. We confirmed the identity of MetO in BALF and used reference calibration to confirm correlation with PRAGMA-%Dis (Spearman’s ρ=0.582, p=0.0029), extending to bronchiectasis (PRAGMA-%Bx; ρ=0.698, p=1.5×10−4), airway neutrophils (ρ=0.569, p=0.0046) and BALF MPO (ρ=0.803, p=3.9×10−6). BALF MetO associates with structural lung damage, airway neutrophils and MPO in early CF. Further studies are needed to establish whether methionine oxidation directly contributes to early CF lung disease and explore potential therapeutic targets indicated by these findings.

Copyright information:

©ERS 2018.

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