Metabolomics Reveals Inflammatory-Linked Pulmonary Metabolic Alterations in a Murine Model of House Dust Mite-Induced Allergic Asthma

Abstract

Although the house dust mite (HDM) is a major environmental aeroallergen that promotes the pathogenesis and severity of allergic asthma, it remains elusive if HDM exposures can induce global metabolism aberrations during allergic airway inflammation. Using an integrated gas and liquid chromatography mass spectrometry-based metabolomics and multiplex cytokine profile analysis, metabolic alterations and cytokine changes were investigated in the bronchoalveolar lavage fluid (BALF), serum, and lung tissues in experimental HDM-induced allergic asthma. Allergic pulmonary HDM exposures lead to pronounced eosinophilia, neutrophilia, and increases in inflammatory cytokines. Metabolomics analysis of the BALF, serum, and lung tissues revealed distinctive compartmental metabolic signatures, which included depleted carbohydrates, increased energy metabolites, and consistent losses of sterols and phosphatidylcholines. Pearson correlation analysis uncovered strong associations between specific metabolic alterations and inflammatory cells and cytokines, linking altered pulmonary metabolism to allergic airway inflammation. The clinically prescribed glucocorticoid prednisolone could modulate airway inflammation but was ineffective against the reversal of many HDM-induced metabolic alterations. Collectively, metabolomics reveal comprehensive pulmonary metabolic signatures in HDM-induced allergic asthma, with specific alterations in carbohydrates, lipids, sterols, and energy metabolic pathways. Altered pulmonary metabolism may be a major underlying molecular feature involved during HDM-induced allergic airway inflammation, linked to inflammatory cells and cytokines changes.

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

“…Recently, our laboratory has reported the first metabolomics study on BALF from mouse asthma, and revealed major changes in carbohydrates, sterols and energy metabolites . Our subsequent followup metabolomics study of house dust mite-induced allergic asthma similarly demonstrated corroborating and comprehensive evidences of altered pulmonary metabolism in the lung tissues, BALF and serum (Ho et al 2014b). The present study investigated the metabolomics of serum from asthma mice, and evaluated potential restorative effects of artesunate in BALF and serum metabolome of allergic asthma in comparison with dexamethasone.…”

“…Metabolomics refers to the global investigation of metabolites in biological systems (comparing normal to disease) (Xu et al 2014), and has been applied to allergic asthma to profile metabolic changes and identify disease biomarkers (Lara et al 2008;Ho et al 2013Ho et al , 2014bSaude et al 2009Saude et al , 2011Mattarucchi et al 2012;Jung et al 2013). We have recently uncovered novel disease-relevant metabolic changes in the bronchoalveolar lavage fluid (BALF) from experimental mouse asthma, which involved major losses of sugars with resultant increases in energy metabolites and reductions of sterols (Ho et al , 2014b.…”

“…We have recently uncovered novel disease-relevant metabolic changes in the bronchoalveolar lavage fluid (BALF) from experimental mouse asthma, which involved major losses of sugars with resultant increases in energy metabolites and reductions of sterols (Ho et al , 2014b. In the earlier study, dexamethasone reversed most metabolic alterations in allergic airway inflammation, but also induced considerable changes in other metabolites irrelevant to asthma pathogenesis.…”

Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation

“…Previous metabolomics studies revealed metabolic alteration in the asthma exacerbated condition [32,[34][35][36]. Histidine, trimethylamine N-oxide, phenylacetylglycine, threonine, 4-aminohippurate and methylamine were decreased, whereas creatine, glucose, hippurate, alanine, glycolate, succinate, myo-inositol, dimethylamine, formate, homovanillate, acetylcarnitine, taurine, lactate, oxaloacetate, cis-aconitate, 2-methylglutarate, tyrosine, 1-methylhistamine, 2-hydroxyisobutyrate, acetone, carnitine, 3-methyladipate and 2-oxoglutarate were increased in asthmatic children during acute exacerbation.…”

Vitamin E Isoform γ-Tocotrienol Downregulates House Dust Mite–Induced Asthma

“…Female BALB/c mice 6-8 wk of age (Animal Resources Center, Canning Vale, Western Australia, Australia) were anesthetized with isoflurane (Halocarbon Products, River Edge, NJ) and given 40 ml HDM (100 mg Dermatophagoides pteronyssinus extracts, Greer Laboratories, Lenoir, NC) or saline as a negative control on days 0, 7, and 14 via intratracheal route as described (15,16). Because the NOAEL for tocotrienols was reported at 260 mg/kg daily in mice for 13 wk or up to 1 y (12)(13)(14), the highest oral dose of vitamin E isoforms in this study was capped at 250 mg/kg.…”