Introduction
Asthma is a serious global health problem of chronic inflammatory airway disease , which is characterized by airway hyperresponsiveness and reversible airway obstruction resulting in recurrent episodes of wheezing, shortness of breath, chest tightness, and cough1. Asthma is a heterogeneous disease with different phenotypes and endotypes, within which the inflammatory phenotypes of asthma (eosinophilic asthma [EA], neutrophilic asthma [NA], and paucigranulocytic asthma [PGA]) are widely recognized by differential proportions of induced sputum granulocytes2. Although some guidelines recommend tailored management approaches for patients with different inflammatory phenotypes1,3,4, treatment strategy for specific inflammatory phenotypes especially neutrophilic asthma is lacking and represents an unmet medical need in asthma5,6Meanwhile, the molecular mechanisms driving different inflammatory phenotypes asthma are poorly understood and are likely heterogeneous. Therefore, it is important to identify the specific biomarkers and to understand the molecular mechanism of different inflammatory phenotypes of asthma, which may lead to more personalized medicine7.
Metabolomics is the systematic identification and quantitation scientific study of chemical processes involving metabolites, small molecule substrates, intermediates and products of cell metabolism in a given organism or biological sample8,9. Metabolomics represent an integrated pathophysiological profile encompassing genetic and environmental interactions, which can be instrumental in elucidating the biological mechanisms of asthma. There is growing evidence that metabolomic profiles in exhaled breath condensate (EBC), urine, and blood could distinguish asthma and asthma phenotypes10. Our previous study has also showed for the first time that the metabolite profiles in induced sputum better separate asthma phenotypes11. Although some studies have shown that inflammatory asthma phenotypes can be discriminated by an electronic nose breath analyzer12, there are no specific metabolic biomarkers and molecular pathways identified in terms of different inflammatory asthma phenotypes in the study. Therefore, it can be more justified with the use of induced sputum for studies that aimed at obtaining a close molecular mechanism of different inflammatory asthma phenotypes.
The primary aim of this study was to identify the metabolic signatures and underlying molecular pathways of different inflammatory asthma phenotypes. The secondary aim was to explore if these signatures are related to asthma control and exacerbation. We applied ultra-high performance liquid chromatography–mass spectrometry (UHPLC-MS) to characterize the induced sputum metabolic profiles from healthy controls and asthmatic patients classified by different inflammatory phenotypes as EA, NA and PGA in the discovery set. Following multivariate modelling, the concentrations of selected metabolites were confirmed with targeted mass spectrometry assays in the validation set.