Transcriptomic responses in the lung epithelium upon acute exposure to traffic-related air pollution and allergen

While allergen inhalation has been a primary focus of asthma research, the evidence associating traffic-related air pollution (TRAP) with allergic asthma is growing, but the underlying interactions remain unclear. The airway epithelium is amongst the first cells exposed to TRAP, hence understanding its interactions with TRAP and allergen is important. Diesel exhaust (DE), a paradigm of TRAP, consists of particulate matter (PM) and gases. Modern diesel engines often have catalytic diesel particulate filters (CDPF) to reduce PM output, but these may increase gas release, and its effects on human health remain unclear. We conducted a randomized, double-blinded, crossover study using our unique in vivo human exposure system to investigate the effects of DE and allergen co-exposure, with or without particle depletion to model CDPF, on the airway epithelial transcriptome. Participants were exposed for 2 hours before an allergen inhalation challenge, with each receiving filtered air and saline (FA-S), filtered air and allergen (FA-A), DE and allergen (DE-A), or particle-depleted DE and allergen (PDDE-A), over 4 different occasions, each separated by a 4-week washout period. Endobronchial brushings were collected 48 hours after each exposure and RNA sequenced. Quality was checked and alignment and quantification against a reference transcriptome performed. Differentially expressed genes (DEGs) were identified using DESeq2 followed by GO enrichment and pathway analysis. FA-A, DE-A, and PDDE-A exposures significantly modulated genes relative to FA-S. Therein, 462 DEGs were identified with 6 (↑4, ↓2) modulated by all three conditions; FA-A uniquely modulated the highest number (↑178, ↓155), followed by DE-A (↑44, ↓23), and then PDDE-A exposure (↑15, ↓2). Investigation revealed that FA-A and DE-A exposures modulated gene expression associated with inflammatory responses and that some of these were reduced after particle depletion. Taken together, this thesis provides experimental evidence and novel insights in elucidating transcriptional changes after co-exposure to DE and allergens, with or without particle depletion.Medicine, Faculty ofExperimental Medicine, Division ofGraduat