High-resolution metabolomics to identify urine biomarkers in corticosteroid-resistant asthmatic children

다국어 초록 (Multilingual Abstract)

<P><B>Background</B></P> <P>Corticosteroid (CS) treatment has been established as the first anti-inflammatory treatment for adults and children with asthma. However, a subset of patients fails to respond to combined systemic and inhaled CS treatment.</P> <P><B>Objective</B></P> <P>This study was aimed at further understanding CS resistance among children with severe asthma.</P> <P><B>Methods</B></P> <P>High-resolution metabolomics was performed on urine samples from CS-respondent (n = 15) and CS-nonrespondent (n = 15) children to determine possible urine biomarkers related to CS resistance. The metabolic phenotypes of CS responders and CS nonresponders were analyzed using bioinformatics including Manhattan plot with false- discovery rate, hierarchical cluster analysis, Kyoto Encyclopedia Genes and Genomes, and Mummichog pathway analysis.</P> <P><B>Results</B></P> <P>The 2-way hierarchical cluster analysis study determined 30 metabolites showing significantly different levels between CS responders and CS nonresponders. The important metabolites annotated were 3,6-dihydronicotinic acid (126.05 <I>m</I>/<I>z</I>, RT: 106, [M+H]<SUP>+</SUP>), 3-methoxy-4-hydroxyphenyl(ethylene)glycol (185.05 <I>m</I>/<I>z</I>, RT: 155, [M+H]<SUP>+</SUP>), 3,4-dihydroxy-phenylalanine (198.07 <I>m</I>/<I>z</I>, RT: 446, [M+H]<SUP>+</SUP>), γ-glutamylcysteine (236.06 <I>m</I>/<I>z</I>, RT: 528, [M+S(34)+H]<SUP>+</SUP>), Cys-Gly, (253.06 <I>m</I>/<I>z</I>, RT: 528, [M-NH<SUB>3</SUB>+H]<SUP>+</SUP>), and reduced Flavin mononucleotide (517.0794 <I>m/z</I>, RT: 533, [M+NaCl]<SUP>+</SUP>). Tyrosine metabolism, degradation of aromatic compounds, and glutathione metabolism are suggested to be significant pathways relating to CS resistance.</P> <P><B>Conclusions</B></P> <P>High-resolution metabolomics is a promising approach in asthma research. Five candidate markers were identified to be related to CS-resistant children with severe asthma. These compounds, upon validation, may contribute further in the understanding of CS resistance among children with severe asthma through the use of urine.</P>