Genome-Wide Analysis Reveals Mucociliary Remodeling of the Nasal Airway Epithelium Induced by Urban PM_2.5

Abstract

Air pollution particulate matter ,2.5 mm (PM 2.5 ) exposure is associated with poor respiratory outcomes. Mechanisms underlying PM 2.5 -induced lung pathobiology are poorly understood but likely involve cellular and molecular changes to the airway epithelium. We extracted and chemically characterized the organic and water-soluble components of air pollution PM 2.5 samples, then determined the whole transcriptome response of human nasal mucociliary airway epithelial cultures to a dose series of PM 2.5 extracts. We found that PM 2.5 organic extract (OE), but not water-soluble extract, elicited a potent, dose-dependent transcriptomic response from the mucociliary epithelium. Exposure to a moderate OE dose modified the expression of 424 genes, including activation of aryl hydrocarbon receptor signaling and an IL-1 inflammatory program. We generated an OE-response gene network defined by eight functional enrichment groups, which exhibited high connectivity through CYP1A1, IL1A, and IL1B. This OE exposure also robustly activated a mucus secretory expression program (.100 genes), which included transcriptional drivers of mucus metaplasia (SPDEF and FOXA3). Exposure to a higher OE dose modified the expression of 1,240 genes and further exacerbated expression responses observed at the moderate dose, including the mucus secretory program. Moreover, the higher OE dose significantly increased the MUC5AC/MUC5B gel-forming mucin expression ratio and strongly downregulated ciliated cell expression programs, including key ciliating cell transcription factors (e.g., FOXJ1 and MCIDAS). Chronic OE stimulation induced mucus metaplasia-like remodeling characterized by increases in MUC5AC 1 secretory cells and MUC5AC mucus secretions. This epithelial remodeling may underlie poor respiratory outcomes associated with high PM 2.5 exposure.

Effect of concentration and duration of particulate matter exposure on the transcriptome and DNA methylome of bronchial epithelial cells

“…We next used the GEO database and PubMed to identify other studies that also performed transcriptomic analysis in bronchial epithelial cells after PM exposure ( Table 2 ). These studies utilized PM of varying size (2.5–10 µm) and from different locations [Saudi Arabia ( 15 ), China ( 11 ), United States ( 10 , 13 ), Italy ( 12 )], with treatments ranging from a concentration of 10–50 µg/cm 2 for 24 h. Excluding studies where data were incomplete or not publicly available, we compared the differentially expressed genes found in our study with those identified in other datasets ( Fig. 2 ).…”

“…We also treated cells directly with PM 2.5 dissolved in aqueous medium, and experiments performed using an air–liquid interface may produce different results, as suggested by other studies ( 44 , 45 ). Use of air–liquid interface may also obviate the need to account for how PM 2.5 is extracted, as varying levels of organic fractions has been shown to independently affect transcriptomic results ( 13 ). The lowest concentration we used was 1 µg/cm 2 , which was much lower than many other in vitro studies.…”

Exposure to particulate matter upregulates ACE2 and TMPRSS2 expression in the murine lung

“…It is crucial to discuss which components of PM are responsible for the phenomena observed in this study. In fact, PM is composed of a wide range of chemicals and biological materials such as elemental carbon; organic carbon, including polycyclic aromatic hydrocarbons (PAHs); inorganic salts; metals, and lipopolysaccharide (LPS) (Honda et al, 2017;Montgomery et al, 2020). Notably, LPS has been associated with deleterious effects on respiratory health and immune function (Onishi et al, 2018).…”

Gill Transcriptomic Responses to Toxin-producing Alga Prymnesium parvum in Rainbow Trout

“…The positive relationship between the dose of P. parvum and the number of DEGs points towards an overall sensitivity of the gill transcriptome to toxic algae dose. Dose-dependent transcriptomic effects have also been demonstrated in the gut of Atlantic salmon exposed to plant proteins ( 49 ) and recently in human nasal airway epithelium cultures exposed to air pollution particulate matter < 2.5 μm (PM 2.5 ) ( 62 ). Furthermore, fish from HH and HM groups had not only twice more DEGs identified in their gills relative to LL fish, but also twice as many upstream regulators (26, 28 and 14, respectively) ( Figure 3B ) and twice as many downstream effects (28, 31 and 17, respectively) ( Figure 3C ).…”