Mucus Plugs-associated Gene Expression Identifies Pathophysiology Shared with Chronic Bronchitis

Rationale: Mucus plug formation and chronic bronchitis are manifestations of mucus pathology in chronic obstructive pulmonary disease. Identifying gene expression changes related to mucus pathology could provide insight into its pathogenesis. Objectives: To investigate gene expression changes in individuals with mucus plugs, identify related biological pathways, and assess whether mucus plug-related gene expression associates with clinical features of other mucus pathologies. Methods: We studied 290 participants from the Detection of Early Lung Cancer Among Military Personnel 2 study with mainstem bronchial brush bulk RNA-sequencing data (n = 204 discovery, n = 86 validation). We scored mucus plugging based on the number of lung segments with mucus plugs identified on chest computed tomography scans and used correlative analysis to identify differentially expressed genes and examine their association with chronic bronchitis symptoms. Results: 76 participants (37%) in the discovery set had mucus plugs. Differentially expressed genes were broadly epithelial- or immune-related. Epithelial-related genes show decreased expression of genes involved in cilia maintenance and microtubule function and increased expression of genes related to epithelial maintenance and protection. Expression patterns of epithelial-related genes are associated with chronic bronchitis symptoms. Immune-related genes are enriched for innate and adaptive pathways. Expression of immune genes varies by lung function and was more weakly associated with mucus plugs than that of epithelial-related genes. Findings were replicated in an independent validation set. Conclusion: Several distinct gene expression patterns are linked to the presence of mucus plugs, highlighting biological pathways involved in mucus pathophysiology. Variability in gene expression suggests a spectrum of mucus pathophysiology contributes to mucus plugs and chronic bronchitis symptoms.