Myeloperoxidase oxidation of methionine associates with early cystic fibrosis lung disease

• Type of Material: Article
• Authors: Joshua Chandler, Emory University; Camilla Margaroli, Childrens Healthcare Atlanta; Hamed Horati, Sophia Children’s Hospital; Matthew B. Kilgore, Childrens Healthcare Atlanta; Mieke Veltman, Sophia Children’s Hospital; H. Ken Liu, Emory University; Alexander J. Taurone, Emory University; Limin Peng, Emory University; Lokesh Guglani, Emory University; Karan Uppal, Emory University; Young-Mi Go, Emory University; Harm A. W. M. Tiddens, Sophia Children’s Hospital; Bob J. Scholte, Sophia Children’s Hospital; Rabindra Tirouvanziam, Emory University; Dean Jones, Emory University; Hettie M. Janssens, Sophia Children’s Hospital
• Language: English
• Date: 2018-10-01
• Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©ERS 2018.
• Final Published Version (URL): http://dx.doi.org/10.1183/13993003.01118-2018
• Title of Journal or Parent Work: EUROPEAN RESPIRATORY JOURNAL
• Volume: 52
• Issue: 4
• Grant/Funding Information: 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: Respiratory System; PROTEIN; GLUTATHIONE; OXIDANTS; THIOCYANATE; THERMODYNAMICS; BRONCHIECTASIS; Life Sciences & Biomedicine; METABOLOMICS; Science & Technology; INFLAMMATION; CHILDREN; ABSOLUTE RATE CONSTANTS
• Research Categories: Biology, Biostatistics; Health Sciences, Immunology; Health Sciences, Nutrition

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.