Radical-Containing Ultrafine Particulate Matter Initiates Epithelial-to-Mesenchymal Transitions in Airway Epithelial Cells

Abstract

Environmentally persistent free radicals (EPFRs) in combustiongenerated 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 combustionderived EPFRs elicit in vivo responses remain elusive. In this study, we used a chemically defined EPFR consisting of approximately 0.2 mm 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 mg/cm 2 ) caused substantial necrosis. At low doses (20 mg/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 a-smooth muscle actin (a-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 a-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.Keywords: particulate matter; epithelial-mesenchymal transition; environmental asthma; pediatric Combustion-generated particulate matter (PM) from industrial processes and burning of biomass and fossil fuels has been linked with adverse pulmonary health effects (1). Environmental PM, both fine and ultrafine, is capable of airway deposition, alveolar penetration, respiratory distress, and exacerbation of preexisting pulmonary conditions. Previous studies highlight the potential roles of PM exposure in predisposing to asthma and pulmonary fibrosis (2-4). Additionally, PM has adjuvant effects when combined with innocuous antigen (5-7) and induces cellular damage, stimulating fibrotic remodeling in adult rodent exposure models (2). The developing pulmonary and immune systems are particularly vulnerable (8). We have developed a model for studying particulate exposures in neonatal rodents (, 7 d of age) (9), which we apply here to understand the effects of combustiongenerated environmentally persistent free radicals (EPFRs) on pulmonary airway remodeling.Delineation of the influences of particulate burden from the reactive chemical species complexed with the particulate has proven difficult. The nature of the chemical species drastically influences ...

Fire toxicity – The elephant in the room?

“…This results in surface-stabilized, environmentally persistent free radicals (EPFR), which continue to exist in ambient air from hours to months, and can last at least 12 h in biological fluids. In laboratory animals and human lung cell lines they have been shown to cause the increased oxidative stress resulting in regeneration of reactive oxygen species (ROS) in biological systems, and associated with cancer, pulmonary and other diseases [62,63]. The formation of potentially toxic particulates, polycyclic aromatic hydrocarbons, and isocyanates, and their distribution between gas phase and solid phase for different building material fires has been investigated [47].…”

The Secretome of Human Bronchial Epithelial Cells Exposed to Fine Atmospheric Particles Induces Fibroblast Proliferation

“…Fibrosis can also result from epithelial to mesenchymal transition [21]. It was very recently demonstrated that ultrafine particles containing radicals initiate such a transition in airway epithelial cells [22]. Our further investigations will explore such a possibility.…”

The Effect of Particle Deposition on Immunological Response as Measured by Cytokine Production

“…As previously noted, the deposition of particulate matter is affected by the underlying status of the airways (Kim and Kang, 1997). This includes particulate-induced conditions, already described, as well as conditions such as nonallergic asthma and other disorders that predispose an individual to bronchial hypersensitivity (Nel et al, 1998;Hamada et al, 2000;Nicolai, 2002;Peden, 2002;Weisel, 2002;Whitekus et al, 2002;Hao et al, 2003;Ryman-Rasmussen et al, 2009;Scarino et al, 2012;Thevenot et al, 2012). For example, beryllium sensitivity is believed to be the result of a genetic polymorphism (Santo Tomas, 2009).…”