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Metabolomic Biomarkers in a Model of Asthma Exacerbation

Urine Nuclear Magnetic Resonance

¹ Department of Pediatrics, ² Medical Resonance Diagnostics Centre, ³ Department of Biochemistry, and ⁴ Department of Medicine, University of Alberta, Edmonton, Alberta; and ⁵ Institute for Biodiagnostics, National Research Council Canada, Winnipeg, Manitoba, Canada

Correspondence and requests for reprints should be addressed to Darryl Adamko, M.D., F.R.C.P.C., Pulmonary Research Group, Pediatric Pulmonary Medicine, 550 HMRC, University of Alberta, Edmonton, AB, T6G 2S2 Canada. E-mail: dadamko{at}ualberta.ca

Rationale: Airway obstruction in patients with asthma is associated with airway dysfunction and inflammation. Objective measurements including sputum analysis can guide therapy, but this is often not possible in typical clinical settings. Metabolomics is the study of molecules generated by metabolic pathways. We hypothesize that airway dysfunction and inflammation in an animal model of asthma would produce unique patterns of urine metabolites measured by multivariate statistical analysis of high-resolution proton nuclear magnetic resonance (¹H NMR) spectroscopy data.

Objectives: To develop a noninvasive means of monitoring asthma status by metabolomics and urine sampling.

Methods: Five groups of guinea pigs were studied: control, control treated with dexamethasone, sensitized (ovalbumin, administered intraperitoneally), sensitized and challenged (ovalbumin, administered intraperitoneally, plus ovalbumin aerosol), and sensitized-challenged with dexamethasone. Airway hyperreactivity (AHR) to histamine (administered intravenously) and inflammation were measured. Multivariate statistical analysis of NMR spectra based on a library of known urine metabolites was performed by partial least-squares discriminant analysis. In addition, the raw NMR spectra exported as xy-trace data underwent linear discriminant analysis.

Measurements and Main Results: Challenged guinea pigs developed AHR and increased inflammation compared with sensitized or control animals. Dexamethasone significantly improved AHR. Using concentration differences in metabolites, partial least-squares discriminant analysis could discriminate challenged animals with 90% accuracy. Using only three or four regions of the NMR spectra, linear discriminant analysis–based classification demonstrated 80–90% separation of the animal groups.

Conclusions: Urine metabolites correlate with airway dysfunction in an asthma model. Urine NMR analysis is a promising, noninvasive technique for monitoring asthma in humans.

Key Words: asthma • biomarkers • metabolomics • nuclear magnetic resonance • urine

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Objective measurements of airway inflammation can improve therapy. Development of improved noninvasive diagnostics is considered a valuable area of research. What This Study Adds to the Field In an animal model, 1H NMR spectroscopic analysis of urine metabolites differentiates animals with or without airway inflammation, using a panel of biomarkers. These data suggest that urine NMR analysis could be applied to humans with asthma.