title: Metabolomic profiling reveals biochemical pathways and biomarkers associated with pathogenesis in cystic fibrosis cells.
abstract: Cystic fibrosis (CF) is a life-shortening disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To gain an understanding of the epithelial dysfunction associated with CF mutations and discover biomarkers for therapeutics development, untargeted metabolomic analysis was performed on primary human airway epithelial cell cultures from three separate cohorts of CF patients and non-CF subjects. Statistical analysis revealed a set of reproducible and significant metabolic differences between the CF and non-CF cells. Aside from changes that were consistent with known CF effects, such as diminished cellular regulation against oxidative stress and osmotic stress, new observations on the cellular metabolism in the disease were generated. In the CF cells, the levels of various purine nucleotides, which may function to regulate cellular responses via purinergic signaling, were significantly decreased. Furthermore, CF cells exhibited reduced glucose metabolism in glycolysis, pentose phosphate pathway, and sorbitol pathway, which may further exacerbate oxidative stress and limit the epithelial cell response to environmental pressure. Taken together, these findings reveal novel metabolic abnormalities associated with the CF pathological process and identify a panel of potential biomarkers for therapeutic development using this model system.
authors.affiliation: Cystic Fibrosis Foundation Therapeutics, Inc, Bethesda, Maryland 20814, USA.
authors.forename: Diana R
authors.initials: DR
authors.lastname: Wetmore
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Joseloff
authors.forename: Joseph
authors.initials: J
authors.lastname: Pilewski
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Lee
authors.forename: Kay A
authors.initials: KA
authors.lastname: Lawton
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Mitchell
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
authors.forename: John A
authors.initials: JA
authors.lastname: Ryals
authors.forename: Lining
authors.initials: L
authors.lastname: Guo
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D050260:Carbohydrate Metabolism; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D055432:Metabolomics; D009154:Mutation; D009997:Osmotic Pressure; D018384:Oxidative Stress; D011684:Purine Nucleosides / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; C505032:CFTR protein, human; D011684:Purine Nucleosides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator