Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Aug;148(2):507-515.
doi: 10.1378/chest.14-1800.

Metabolomic Evaluation of Neutrophilic Airway Inflammation in Cystic Fibrosis

Affiliations

Metabolomic Evaluation of Neutrophilic Airway Inflammation in Cystic Fibrosis

Charles R Esther Jr et al. Chest. 2015 Aug.

Abstract

Background: Metabolomic evaluation of cystic fibrosis (CF) airway secretions could identify metabolites and metabolic pathways involved in neutrophilic airway inflammation that could serve as biomarkers and therapeutic targets.

Methods: Mass spectrometry (MS)-based metabolomics was performed on a discovery set of BAL fluid samples from 25 children with CF, and targeted MS methods were used to identify and quantify metabolites related to neutrophilic inflammation. A biomarker panel of these metabolites was then compared with neutrophil counts and clinical markers in independent validation sets of lavage from children with CF and adults with COPD compared with control subjects.

Results: Of the 7,791 individual peaks detected by positive-mode MS metabolomics discovery profiling, 338 were associated with neutrophilic inflammation. Targeted MS determined that many of these peaks were generated by metabolites from pathways related to the metabolism of purines, polyamines, proteins, and nicotinamide. Analysis of the independent validation sets verified that, in subjects with CF or COPD, several metabolites, particularly those from purine metabolism and protein catabolism pathways, were strongly correlated with neutrophil counts and were related to clinical markers, including airway infection and lung function.

Conclusions: MS metabolomics identified multiple metabolic pathways associated with neutrophilic airway inflammation. These findings provide insight into disease pathophysiology and can serve as the basis for developing disease biomarkers and therapeutic interventions for airways diseases.

PubMed Disclaimer

Figures

Figure 1 –
Figure 1 –
MS metabolomics. A, Relationship between neutrophil (PMN) count and total MS signal during discovery metabolomics. Signal for each peak was normalized such that the lowest signal in the dataset had a value of 1. A strong correlation (r = 0.70, P < .001) was observed between neutrophil counts and total MS metabolomics signal. B, Principal component analysis of metabolomic data. Low inflammation samples () generally clustered together away from high inflammation samples (), but with some overlap. MS = mass spectrometry; PC = principal component; PMN = polymorphonuclear leukocyte.
Figure 2 –
Figure 2 –
Biomarkers and infection. A, Differences in BAL fluid (BALF) neutrophil counts were observed among samples with no pathogens on culture (white, n = 5), fungal pathogens only (hatched, n = 5), or bacterial pathogens (gray, n = 15). *P < .05 by analysis of variance (ANOVA), Tukey posttest indicating differences between no pathogen and bacterial pathogen groups. B, Multiple metabolomics biomarkers also differentiated among BALF culture status, including some metabolites (**) that differentiated samples with bacterial pathogens from both no pathogen and fungal pathogen-only groups (Tukey posttest following ANOVA). Hyp = hypoxanthine; Leu = leucine; Leu-Pro = leucine-proline dipeptide; Nic = nicotinamide; NSp = N-acetyl spermidine; Phe = phenylalanine; Spm = spermine; Xan = xanthine. See Figure 1 legend for expansion of other abbreviations.
Figure 3 –
Figure 3 –
BALF biomarkers and lung function. A, Percent predicted FEV1 was significantly negatively correlated with BALF neutrophil (PMN) counts (r = −0.57, P < .01). B, Similar correlations were observed for BALF purines (Hyp, r = −0.56; Xan, r = −0.56; P < .01) and protein catabolism metabolites (Leu, r = −0.61; Phe, r = −0.59; Leu-Pro, r = −0.59; P < .01). C, Correlations with percent predicted FEV1 were observed for polyamines (Spm, r = −0.44, P < .05) with a trend for Nic (r = −0.36, P < .11). D, Ado, but no other metabolite, was negatively correlated with changes in predicted FEV1 over time (r = −0.71, P < .001). Ado = adenosine. See Figure 1 and 2 legends for expansion of other abbreviations.
Figure 4 –
Figure 4 –
Biomarker metabolites in COPD. A, Biomarker metabolites were measured in BALF from healthy nonsmokers (n = 10, white bars), healthy smokers (n = 10, hatched bars), and patients with COPD (n = 10, gray bars). Biomarker metabolites differentiated COPD samples from those of healthy nonsmokers (*) or from both healthy nonsmokers and healthy smokers (**); ANOVA with Tukey posttest. B, Biomarkers Hyp (r = −0.57, P < .001), Leu (r = −0.44, P < .01), and Nic (r = −0.50, P < .01) and others (not shown) were significantly correlated with percent predicted FEV1. See Figure 1 and 2 legends for expansion of abbreviations.

Similar articles

Cited by

References

    1. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992-2001. - PubMed
    1. Alton EW, Davies JC, Geddes DM. Biomarkers for cystic fibrosis: are we progressing? Am J Respir Crit Care Med. 2007;175(8):750-751. - PubMed
    1. Mayer-Hamblett N, Aitken ML, Accurso FJ, et al. Association between pulmonary function and sputum biomarkers in cystic fibrosis. Am J Respir Crit Care Med. 2007;175(8):822-828. - PMC - PubMed
    1. Esther CR, Jr, Alexis NE, Clas ML, et al. Extracellular purines are biomarkers of neutrophilic airway inflammation. Eur Respir J. 2008;31(5):949-956. - PMC - PubMed
    1. Wolak JE, Esther CR, Jr, O’Connell TM. Metabolomic analysis of bronchoalveolar lavage fluid from cystic fibrosis patients. Biomarkers. 2009;14(1):55-60. - PMC - PubMed

Publication types

MeSH terms