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. 2016 Dec;48(6):1612-1621.
doi: 10.1183/13993003.00524-2016. Epub 2016 Nov 11.

Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis

Charles R Esther Jr  1   2 , Lidija Turkovic  3 , Tim Rosenow  3 , Marianne S Muhlebach  4   2 , Richard C Boucher  2 , Sarath Ranganathan  5 , Stephen M Stick  3 ; AREST CF
Affiliations

Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis

Charles R Esther Jr et al. Eur Respir J. 2016 Dec.

Abstract

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.

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Figures

Figure 1
Figure 1
Average MS metabolomics signal in BALF from 20 preschool children with CF plotted relative to % neutrophils on cell counts from these samples. Samples with >60% neutrophils had more overall MS signal.
Figure 2
Figure 2
Metabolite concentrations for various metabolites in lobes with bronchial wall thickening (BWT), bronchiectasis (BE), or neither BWT or BE (None) by CF-CT scoring system. *=p<0.05 by multivariate analysis.
Figure 3
Figure 3
ROC curves demonstrating the sensitivity and specificity for various metabolites relative to neutrophil elastase (NE, marked as ‘X’) in predicting future bronchiectasis. A. Purine metabolites adenosine (Ado, open circles) and hypoxanthine (Hyp, open triangles). B. Protein catabolism metabolites phenylalanine (Phe, filled circles) and the dipeptide Leu-Pro (filled triangles).
Figure 4
Figure 4
Adenosine metabolic activity in BALF from preschool children with CF was assessed as the ability to generate hypoxanthine (Hyp) from exogenously added adenosine (Ado). Samples with no significant bronchitis (<40% neutrophils) had no significant activity, whereas activity was readily detected in samples with bronchitis (>60% neutrophils). BALF from clinically stable preschoolers with bronchiectasis (BE) on chest CT showed moderate levels of adenosine metabolic activity. N=3–4 per group. * = p<0.01 by Mann-Whitney, with significant post tests for bronchitis and BE groups relative to no bronchitis.
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