Abstract
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.
Abstract
Identifying molecules associated with early cystic fibrosis lung disease may lead to new means of limiting progression. We found that airway fluid methionine sulfoxide produced by myeloperoxidase associates with lung disease in CF patients aged 1–3 years.
Footnotes
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Conflict of interest: Dr. Chandler reports grants from National Institutes of Health, grants from Cystic Fibrosis Foundation, outside the submitted work.
Conflict of interest: Dr. Margaroli reports grants from NIH R01HL126603, grants from CF@LANTA RDP Fellowship, during the conduct of the study.
Conflict of interest: Dr. Horati reports grants from NIH, outside the submitted work.
Conflict of interest: Dr. Kilgore has nothing to disclose.
Conflict of interest: Dr. Veltman has nothing to disclose.
Conflict of interest: Dr. Liu has nothing to disclose.
Conflict of interest: Mr. Taurone has nothing to disclose.
Conflict of interest: Dr. Peng reports grants from NIH, outside the submitted work.
Conflict of interest: Dr. Guglani has nothing to disclose.
Conflict of interest: Dr. Uppal has nothing to disclose.
Conflict of interest: Dr. Go has nothing to disclose.
Conflict of interest: Dr. Tiddens reports other from Roche, other from Novartis, grants from CFF, grants from Vertex, grants from Gilead, grants from Chiesi, outside the submitted work; In addition, Dr. Tiddens has a patent Vectura licensed, and a patent PRAGMA-CF scoring system issued and I am heading the Erasmus MC-Sophia Children's Hospital core laboratory LungAnalysis.
Conflict of interest: Dr. Scholte reports grants from ERARE, grants from ZONMW , grants from NIH, during the conduct of the study; and A previous study (Veltman et al 2016) describing S1P metabolism in Cf mutant mice was partially funded by a research grant ($50.0000) and compound (S1Plyase inhibitor) from Lexicon Pharmaceuticals, Inc., The Woodlands, Texas. The MTA granted Erasmus MC unconditional publication rights..
Conflict of interest: Dr. Tirouvanziam reports grants from NIH R01HL126603 and R01HL126603-02S1, during the conduct of the study; personal fees from Celtaxsys, Inc., outside the submitted work.
Conflict of interest: Dr. Jones has nothing to disclose.
Conflict of interest: Dr. Janssens reports grants from NIH, grants from Dutch CF foundation, during the conduct of the study; other from Vertex, grants from Sophia Foundation for research, outside the submitted work.
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