title: Radical-containing ultrafine particulate matter initiates epithelial-to-mesenchymal transitions in airway epithelial cells.
abstract: Environmentally persistent free radicals (EPFRs) in combustion-generated particulate matter (PM) are capable of inducing pulmonary pathologies and contributing to the development of environmental asthma. In vivo exposure of infant rats to EPFRs demonstrates their ability to induce airway hyperresponsiveness to methacholine, a hallmark of asthma. However, the mechanisms by which combustion-derived EPFRs elicit in vivo responses remain elusive. In this study, we used a chemically defined EPFR consisting of approximately 0.2 μm amorphrous silica containing 3% cupric oxide with the organic pollutant 1,2-dichlorobenzene (DCB-230). DCB-230 possesses similar radical content to urban-collected EPFRs but offers several advantages, including lack of contaminants and chemical uniformity. DCB-230 was readily taken up by BEAS-2B and at high doses (200 μg/cm(2)) caused substantial necrosis. At low doses (20 μg/cm(2)), DCB-230 particles caused lysosomal membrane permeabilization, oxidative stress, and lipid peroxidation within 24 hours of exposure. During this period, BEAS-2B underwent epithelial-to-mesenchymal transition (EMT), including loss of epithelial cell morphology, decreased E-cadherin expression, and increased α-smooth muscle actin (α-SMA) and collagen I production. Similar results were observed in neonatal air-liquid interface culture (i.e., disruption of epithelial integrity and EMT). Acute exposure of infant mice to DCB-230 resulted in EMT, as confirmed by lineage tracing studies and evidenced by coexpression of epithelial E-cadherin and mesenchymal α-SMA proteins in airway cells and increased SNAI1 expression in the lungs. EMT in neonatal mouse lungs after EPFR exposure may provide an explanation for epidemiological evidence supporting PM exposure and increased risk of asthma.
authors.affiliation: Louisiana State University Health Sciences Center, Department of Pharmacology & Experimental Therapeutics, New Orleans, LA 70112, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Thevenot
authors.forename: Jordy
authors.initials: J
authors.lastname: Saravia
authors.forename: Nili
authors.initials: N
authors.lastname: Jin
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Giaimo
authors.forename: Regina E
authors.initials: RE
authors.lastname: Chustz
authors.forename: Sarah
authors.initials: S
authors.lastname: Mahne
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Kelley
authors.forename: Valeria Y
authors.initials: VY
authors.lastname: Hebert
authors.forename: Barry
authors.initials: B
authors.lastname: Dellinger
authors.forename: Tammy R
authors.initials: TR
authors.lastname: Dugas
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: Demayo
authors.forename: Stephania A
authors.initials: SA
authors.lastname: Cormier
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D055745:Bronchioles / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D002463:Cell Membrane Permeability; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D051379:Mice; D018384:Oxidative Stress; D010316:Particle Size
chemical_list: D000393:Air Pollutants