Abstract Rationale Cigarette smoke (CS) exposure, whether through active smoking or secondhand smoke, is a well-established risk factor for the development of chronic obstructive pulmonary disease (COPD). In addition to its role in disease pathogenesis, CS exposure significantly increases susceptibility to respiratory infections. Despite extensive epidemiological evidence linking smoke exposure to heightened infection risk, the underlying molecular mechanisms remain poorly defined. Methods In the current study, we have begun investigating transcriptomic differences in primary human nasal epithelial cells (HNECs) collected from nasal brushings of subjects self-identified as never smoking (nonsmokers) or current cigarette smokers (smokers). We isolated RNA from ten nonsmokers and seven smokers for bulk RNA sequencing. Differential gene expression was assessed using DESeq2 and pathway enrichment identified using GO, KEGG, and Reactome analysis. Cellular deconvolution was performed using CIBERSORTx with the human lung cell atlas nose cell type as a reference signature to estimate cell type proportions. Results There were 3344 upregulated differentially expressed genes (DEGs) and 3129 downregulated DEGs in smokers compared to nonsmokers. The top three upregulated DEGs were CYP1A1, CYP1B1, and AC087239.1. The top three downregulated DEGs were ALPG, DPYS, and MOGAT2. Interestingly, genes involved in host defense, such as ITGA2, ITGB1, TRAF5, and TRAF6, were also significantly downregulated. In line with this, downregulated biological processes from HNECs of smokers compared to nonsmokers included MAPK, TGF-B, and NF-kB signaling, and innate immune responses. Using cellular deconvolution of the transcriptomic data, we identified primarily basal, ciliated, club, and goblet epithelial cells from the HNEC samples that were analyzed, with no discernable differences between smokers and nonsmokers. Conclusions Many transcriptomic changes were associated with current smoking status in nasal epithelial cells. Genes known to be overexpressed in smokers, such as CYP1A1, CYP1B1, and MUC5AC, were also upregulated in our dataset. However, the decreased expression of integrins and host defense factors from HNECs of smokers suggests they may be more susceptible to respiratory infections. Further studies validating these findings, such as examining in vitro smoker versus nonsmoker HNEC responses to pathogen infections and additional analysis of the subject’s serum biomarkers such as club cell secretory protein (CC16), are needed. This abstract is funded by: T32ES007091, HL142769, AI178782, P30 ES006694
Hellinger et al. (Fri,) studied this question.