Am J Respir Cell Mol Biol. 2013 Feb;48(2):204-11.

Metabolomics Reveals Altered Metabolic Pathways in Experimental Asthma

*Wanxing Eugene Ho1,2, *Yong-Jiang Xu1, Fengguo Xu3, Chang Cheng4,5, Hong Yong Peh4,5, Steven R. Tannenbaum2,6, W.S. Fred Wong4,5, and Choon Nam Ong1,7.

*These authors contributed equally to this work.

1Saw Swee Hock School of Public Health, National University Health System, Singapore;2Singapore-MIT Alliance for Research and Technology (SMART), Singapore; 3Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing, China; 4Immunology Program, Life Science Institute, National University of Singapore, Singapore; 5Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore;  6Department of Biological Engineering and Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA; 7NUS Environmental Research Institute, National University of Singapore, Singapore.

 

ABSTRACT

Rationale: Metabolomics refers to the comprehensive analysis of metabolites in biological systems and has been employed to study asthmatic patients based on their urinary metabolite profile. We hypothesize that airway allergic asthma would affect metabolism in the lungs, and could be detected in bronchoalveolar lavage fluid (BALF) using a combined liquid chromatography (LC)- and gas chromatography (GC)- mass spectrometry (MS) platform.

Objectives: To investigate changes of lung metabolism in allergic asthma by metabolomic analysis of BALF.

Methods: BALB/c mice were sensitized and challenged with ovalbumin to develop experimental asthma. Dexamethasone was administered to study the effects of corticosteroids on lung metabolism. Metabolites in BALF were measured using LC-MS and GC-MS, and multivariate statistical analysis was performed by orthogonal projections to latent structures discriminant analysis.

Measurements and Main Results: Metabolomic analysis of BALF from ovalbumin-challenged mice revealed novel changes in metabolic pathways in the lungs as compared to control animals. These metabolite changes suggest alterations of energy metabolism in asthmatic lungs, with increases of lactate, malate and creatinine and reductions in carbohydrates such as mannose, galactose and arabinose. Lipid and sterol metabolism were affected with significant decreases in phosphatidylcholines, diglycerides, triglycerides, cholesterol, cortol and cholic acid. Dexamethasone treatment effectively reversed many key metabolite changes, but was ineffective in repressing lactate, malate and creatinine and induced additional metabolite changes.

Conclusions: Metabolomic analysis of BALF offered a promising approach to investigate allergic asthma. Our overall findings revealed considerable pathway changes in lung metabolism in asthmatic lungs, including energy, amino acids and lipid metabolism.

Key words: Metabolome; corticosteroids; mass spectrometry; liquid chromatography; gas chromatography; inflammation

PMID: 23144334

 

Scientific Knowledge on the Subject

Metabolomics has been shown to be a promising technique for the identification of asthmatic patients based on their metabolite profiles. Our findings suggest that there are significant metabolism changes in asthmatic lungs which can be detected in the bronchoalveolar lavage fluid using metabolomics.

What This Study Adds to the Field

This study shows that metabolomic analysis of bronchoalveolar lavage fluid can provide an in-depth understanding of altered lung metabolism in asthma and elucidate unique disease-relevant metabolite profiles. Corticosteroids can help restore certain lung metabolism, but also induce additional metabolite changes.

The study explained

Metabolomics is an upcoming analytical and diagnosis technology, progressively being utilized to study allergic asthma and related respiratory diseases. There is a current lack of metabolomics investigations which studied metabolic changes directly in allergic-inflamed lungs and may help to validate existing metabolomics studies and can potentially identify novel disease-related metabolic signatures and mechanisms.

In this study, we hypothesized that the airway inflammation will alter metabolism in the allergic-inflamed lungs and can be detected in the bronchoalveolar lavage fluid (BALF) via a gas chromatography (GC-) and liquid chromatography (LC-) mass spectrometry (MS) based metabolomics analysis. Female BALB/c mice were sensitized and challenged with ovalbumin to develop experimental allergic asthma. Dexamethasone was also administered to study the metabolic effects of clinically-prescribed corticosteroids on lung metabolism.

Metabolomics analysis of BALF from aeroallergen-challenged animals revealed notable alterations in metabolic profiles and relevant classes of metabolites. These metabolite changes indicate shifts of energy metabolism in asthmatic lungs, with increases of lactate, malate and creatinine and corresponding reductions in carbohydrates such as mannose, galactose and arabinose. Lipid and sterol metabolism were affected with significant decreases in phosphatidylcholines, diglycerides, triglycerides, cholesterol, cortol and cholic acid. Pearson correlation analysis further revealed considerable statistical associations between the altered BALF metabolites and various inflammatory cells, further suggesting that these detected metabolites could be inflammatory-related metabolic alterations. While dexamethasone treatment could effectively reverse many key metabolite changes, the corticosteroid was ineffective in repressing lactate, malate and creatinine and induced additional metabolite changes.

Our overall findings revealed considerable pathway changes in lung metabolism in asthmatic lungs, including energy, amino acids and lipid metabolism. We believe metabolomics, especially metabolomics analysis of the BALF, is a promising approach to identify unique disease-relevant metabolic signatures and mechanisms of allergic asthma and related respiratory diseases.

 

Grant Support and Acknowledgements

This research work was supported in part by: BMRC 09/1/21/19/595 to W.S.F.W. from the BioMedical Research Council of Singapore; NUS Environmental Research Institute and Centre for Environmental and Occupational Health Research.

Wanxing Eugene Ho is a recipient of the Singapore-MIT Alliance (SMA) Graduate Fellowship. The authors would like to thank NERI-Agilent Research Alliance for their technical support.

OCN Fig 1

Figure 1: Overview of Flow of Experimental Analysis and Key Findings.

 

OCN Fig 2

Figure 2: Heatmap of Key BALF Metabolite Changes and Potential Biological Implications in Allergic Asthma. Figure adapted from article, W.E. Ho et. al. Am J Respir Cell Mol Biol.2013 Feb;48(2):204-211.

 

OCN Fig 3

Figure 3: Altered Metabolic Pathways in Experimental Allergic Airway Inflammation and Effects of Dexamethasone Treatment. Figure as featured in article, W.E. Ho et. al. Am J Respir Cell Mol Biol.2013 Feb;48(2):204-211.

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