Abstract Rationale Mismatch of airway to lung size has been implicated in chronic obstructive pulmonary disease (COPD) pathophysiology, whether arising from disproportioned growth or from acquired pathologies over the life course. Lower airway-to-lung ratio (ALR), assessed reproducibly via computed tomography (CT) as the mean airway lumen diameters (trachea-to-subsegments) divided by the cubed root of lung volume, is associated with COPD risk and mortality (all-cause, respiratory, cardiovascular, lung cancer). We sought to characterize the airway biology associated with lower ALR by profiling bronchial gene expression across current and former smokers. Methods We leveraged clinical, radiologic, and bronchial epithelial RNA sequencing data from the SPIROMICS (SubPopulations and Intermediate Outcomes Measures in COPD Study) Phase 1 Bronchoscopy Sub-study (n = 161). To analyze transcriptional differential expression (DE) between participants based on CT-assessed ALR, we utilized DESeq2 and then identified impacted pathways by Ingenuity Pathway Analysis (IPA). Generating cell-type transcriptional signatures from lung and blood single cell sequencing atlases, we also assessed association of ALR with differences in airway cellular composition. Results Across all ever-smokers, after adjustment for age, sex, height, COPD status, smoking status, and pack-years, n = 1,324 genes from airway epithelial samples exhibited DE at a false discovery rate (FDR) 0.2. Per IPA, enriched pathways associated with lower ALR included neutrophilic degranulation and macrophage activity. In cell type analysis, lower ALR was associated with higher signatures of macrophages, neutrophils, dendritic cells, and B cells, and lower ciliated and club cell signatures. When we repeated DE analysis using the same covariate adjustments plus an interaction term for ALR and smoking, n = 713 DE genes were identified at FDR 0.2; the association of DE with lower ALR was overwhelmingly in current rather than former smokers (3699 vs. 2 genes). By pathway and cell type analyses, the association between lower ALR and heightened inflammation (greater macrophage and neutrophil signaling) and epithelial dysregulation (downregulated ciliated and club cell function) was primarily restricted to current smokers. Conclusions In adult ever-smokers, lower ALR is associated with transcriptomic evidence of heightened neutrophil- and macrophage-driven airway inflammation and reduced ciliated and club cell expression, associations that were most evident among current smokers. Whether these cross-sectional patterns, which suggest impaired mucociliary defense and a diminished capacity to clear inhaled particulates, are the result of pre-existing reduced ALR, its cause, or both, will require further investigation. This abstract is funded by: SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C, 75N92024D00012), grants from the NIH/NHLBI (U01HL137880, U24HL141762, R01HL182622, R01HL144718, and R01HL093081), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from Amgen; AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; Genentech; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; MGC Diagnostics; Novartis Pharmaceuticals Corporation; Nycomed GmbH; Polarean; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; Theravance Biopharma; Verona; and Mylan/Viatris.
Kelly et al. (Fri,) studied this question.