title: Dysregulation of metabolic pathways in a mouse model of allergic asthma.
abstract: BACKGROUND
  Asthma is a complex lung disease resulting from the interplay of genetic and environmental factors. To understand the molecular changes that occur during the development of allergic asthma without genetic and environmental confounders, an experimental model of allergic asthma in mice was used. Our goals were to (1) identify changes at the small molecule level due to allergen exposure, (2) determine perturbed pathways due to disease, and (3) determine whether small molecule changes correlate with lung function.
  
  
  METHODS
  In this experimental model of allergic asthma, matched bronchoalveolar lavage (BAL) fluid and plasma were collected from three groups of C57BL6 mice (control vs sensitized and/or challenged with ovalbumin, n=3-5/group) 6 hour, 24 hour, and 48 hour after the last challenge. Samples were analyzed using liquid chromatography-mass spectrometry-based metabolomics. Airway hyper-responsiveness (AHR) measurements and differential cell counts were performed.
  
  
  RESULTS
  In total, 398 and 368 dysregulated metabolites in the BAL fluid and plasma of sensitized and challenged mice were identified, respectively. These belonged to four, interconnected pathways relevant to asthma pathogenesis: sphingolipid metabolism (P=6.6×10-5), arginine and proline metabolism (P=1.12×10-7), glycerophospholipid metabolism (P=1.3×10-10), and the neurotrophin signaling pathway (P=7.0×10-6). Furthermore, within the arginine and proline metabolism pathway, a positive correlation between urea-1-carboxylate and AHR was observed in plasma metabolites, while ornithine revealed a reciprocal effect. In addition, agmatine positively correlated with lung eosinophilia.
  
  
  CONCLUSIONS
  These findings point to potential targets and pathways that may be central to asthma pathogenesis and can serve as novel therapeutic targets.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.|Immunology & Microbiology Department School of Medicine, University of Colorado Denver, Aurora, CO, USA.
authors.forename: K D
authors.identifier: http://orcid.org/0000-0002-3791-8128
authors.initials: KD
authors.lastname: Quinn
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, USA.
authors.forename: M
authors.initials: M
authors.lastname: Schedel
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Nkrumah-Elie
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, USA.
authors.forename: A
authors.initials: A
authors.lastname: Joetham
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.
authors.forename: M
authors.initials: M
authors.lastname: Armstrong
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.
authors.forename: C
authors.initials: C
authors.lastname: Cruickshank-Quinn
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.
authors.forename: R
authors.initials: R
authors.lastname: Reisdorph
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, USA.
authors.forename: E W
authors.initials: EW
authors.lastname: Gelfand
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.|Immunology & Microbiology Department School of Medicine, University of Colorado Denver, Aurora, CO, USA.
authors.forename: N
authors.initials: N
authors.lastname: Reisdorph
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism; D001249:Asthma / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid; D020404:Glycerophospholipids / Q000378:metabolism; D006967:Hypersensitivity / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism
chemical_list: D020404:Glycerophospholipids; D009414:Nerve Growth Factors; D013107:Sphingolipids; D001120:Arginine; D011392:Proline
keywords: allergy; animal models; asthma; mass spectrometry; metabolomics