Chandler et al. article in European Respiratory Journal
"Myeloperoxidase oxidation of methionine associates with early cystic fibrosis lung disease." Chandler JD, Margaroli C, Horati H, Kilgore MB, Veltman M, Liu HK, Taurone AJ, Peng L, Guglani L, Uppal K, Go YM, Tiddens HAWM, Scholte BJ, Tirouvanziam R, Jones DP, Janssens HM. Eur Respir J. 2018 Sep 6. pii: 1801118.
Rationale: 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.
Methods: CF patients aged 12-38 months (n=24; 3/24 later denoted as CF screen positive, inconclusive diagnosis) received chest computed tomography scans, scored by the PRAGMA-CF method to quantify total lung damage (PRAGMA-%Dis) and components such as bronchiectasis. Small molecules in bronchoalveolar lavage fluid (BALF) were measured with high-resolution, accurate-mass metabolomics. Myeloperoxidase was quantified by ELISA and activity assays.
Results: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, a product of methionine oxidation by myeloperoxidase-derived oxidants. We confirmed the identity of methionine sulfoxide 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 myeloperoxidase (ρ=0.803, p=3.9×10-6).
Conclusions: BALF methionine sulfoxide associates with structural lung damage, airway neutrophils and myeloperoxidase 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.