Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis.
Neutrophilic airway inflammation plays a role in early structural lung disease in cystic fibrosis, but the mechanisms underlying this pathway are incompletely understood.Metabolites associated with neutrophilic inflammation were identified by discovery metabolomics on bronchoalveolar lavage fluid supernatant from 20 preschool children (2.9±1.3 years) with cystic fibrosis. Targeted mass-spectrometric detection of relevant metabolites was then applied to 34 children (3.5±1.5 years) enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) who underwent chest computed tomography and bronchoalveolar lavage from two separate lobes during 42 visits. Relationships between metabolites and localised structural lung disease were assessed using multivariate analyses.Discovery metabolomics identified 93 metabolites associated with neutrophilic inflammation, including pathways involved in metabolism of adenyl purines, amino acids and small peptides, cellular energy and lipids. In targeted mass spectrometry, products of adenosine metabolism, protein catabolism and oxidative stress were associated with structural lung disease and predicted future bronchiectasis, and activities of enzymes associated with adenosine metabolism were elevated in the samples with early disease.Metabolomics analyses revealed metabolites and pathways altered with neutrophilic inflammation and destructive lung disease. These pathways can serve as biomarkers and potential therapeutic targets for early cystic fibrosis lung disease.
Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Charles_Esther@med.unc.edu.|Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Charles R
CR
Esther
Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, Australia.
Lidija
L
Turkovic
Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, Australia.
Tim
0000-0003-3727-5131
T
Rosenow
Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Marianne S
MS
Muhlebach
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Richard C
RC
Boucher
Murdoch Children's Research Institute, University of Melbourne, Parkville, Australia.
Sarath
S
Ranganathan
Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, Australia.
Stephen M
SM
Stick
D000241:Adenosine / Q000378:metabolism*; D001315:Australia; D015415:Biomarkers / Q000378:metabolism; D001987:Bronchiectasis / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000150:complications*; D005260:Female; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000378:metabolism*; D016014:Linear Models; D050356:Lipid Metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics; D015999:Multivariate Analysis; D009504:Neutrophils / Q000378:metabolism*; D018384:Oxidative Stress; D011379:Prognosis
D015415:Biomarkers; D000241:Adenosine