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.