title: The Diacetyl-Exposed Human Airway Epithelial Secretome: New Insights into Flavoring-Induced Airways Disease.
abstract: Bronchiolitis obliterans (BO) is an increasingly important lung disease characterized by fibroproliferative airway lesions and decrements in lung function. Occupational exposure to the artificial food flavoring ingredient diacetyl, commonly used to impart a buttery flavor to microwave popcorn, has been associated with BO development. In the occupational setting, diacetyl vapor is first encountered by the airway epithelium. To better understand the effects of diacetyl vapor on the airway epithelium, we used an unbiased proteomic approach to characterize both the apical and basolateral secretomes of air-liquid interface cultures of primary human airway epithelial cells from four unique donors after exposure to an occupationally relevant concentration (∼1,100 ppm) of diacetyl vapor or phosphate-buffered saline as a control on alternating days. Basolateral and apical supernatants collected 48 h after the third exposure were analyzed using one-dimensional liquid chromatography tandem mass spectrometry. Paired t tests adjusted for multiple comparisons were used to assess differential expression between diacetyl and phosphate-buffered saline exposure. Of the significantly differentially expressed proteins identified, 61 were unique to the apical secretome, 81 were unique to the basolateral secretome, and 11 were present in both. Pathway enrichment analysis using publicly available databases revealed that proteins associated with matrix remodeling, including degradation, assembly, and new matrix organization, were overrepresented in the data sets. Similarly, protein modifiers of epidermal growth factor receptor signaling were significantly altered. The ordered changes in protein expression suggest that the airway epithelial response to diacetyl may contribute to BO pathogenesis.
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine.
authors.forename: David M
authors.initials: DM
authors.lastname: Brass
authors.affiliation: 2 National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: William M
authors.initials: WM
authors.lastname: Gwinn
authors.affiliation: 3 Department of Medicine, and.
authors.forename: Ashlee M
authors.initials: AM
authors.lastname: Valente
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine.
authors.forename: Francine L
authors.initials: FL
authors.lastname: Kelly
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine.
authors.forename: Christie D
authors.initials: CD
authors.lastname: Brinkley
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Nagler
authors.affiliation: 4 Proteomics and Metabolomics Shared Resource, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: M Arthur
authors.initials: MA
authors.lastname: Moseley
authors.affiliation: 2 National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Morgan
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Palmer
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine.|4 Proteomics and Metabolomics Shared Resource, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Foster
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D003931:Diacetyl / Q000633:toxicity*; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005421:Flavoring Agents / Q000633:toxicity*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000378:metabolism* / Q000473:pathology; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005421:Flavoring Agents; D020543:Proteome; D066246:ErbB Receptors; D003931:Diacetyl
keywords: 2,3-butanedione; bronchiolitis obliterans; diacetyl; occupational lung disease; proteomics