Bronchial gene expression alterations associated with radiological bronchiectasis
Ke Xu, Alejandro A. Díaz, Fenghai Duan, Minyi Lee, Xiaohui Xiao, Hanqiao Liu, Gang Liu, Michael H. Cho, Adam C. Gower, Yuriy O. Alekseyev, Avrum Spira, Denise R. Aberle, George R. Washko, Ehab Billatos, Marc E. Lenburg
Abstract
Objectives Discovering airway gene expression alterations associated with radiological bronchiectasis may improve the understanding of the pathobiology of early-stage bronchiectasis. Methods Presence of radiological bronchiectasis in 173 individuals without a clinical diagnosis of bronchiectasis was evaluated. Bronchial brushings from these individuals were transcriptomically profiled and analysed. Single-cell deconvolution was performed to estimate changes in cellular landscape that may be associated with early disease progression. Results 20 participants have widespread radiological bronchiectasis (three or more lobes). Transcriptomic analysis reflects biological processes associated with bronchiectasis including decreased expression of genes involved in cell adhesion and increased expression of genes involved in inflammatory pathways (655 genes, false discovery rate <0.1, log 2 fold-change >0.25). Deconvolution analysis suggests that radiological bronchiectasis is associated with an increased proportion of ciliated and deuterosomal cells, and a decreased proportion of basal cells. Gene expression patterns separated participants into three clusters: normal, intermediate and bronchiectatic. The bronchiectatic cluster was enriched by participants with more lobes of radiological bronchiectasis (p<0.0001), more symptoms (p=0.002), higher SERPINA1 mutation rates (p=0.03) and higher computed tomography derived bronchiectasis scores (p<0.0001). Conclusions Genes involved in cell adhesion, Wnt signalling, ciliogenesis and interferon-γ pathways had altered expression in the bronchus of participants with widespread radiological bronchiectasis, possibly associated with decreased basal and increased ciliated cells. This gene expression pattern is not only highly enriched among individuals with radiological bronchiectasis, but also associated with airway-related symptoms in those without discernible radiological bronchiectasis, suggesting that it reflects a bronchiectasis-associated, but non-bronchiectasis-specific lung pathophysiological process.