Lung transcriptomics of emphysema reveal barrier function impairment and macrophage M1-M2 imbalance

<bold>Rationale:</bold> While many studies have examined gene expression in lung tissue, the gene regulatory processes underlying emphysema are still not well understood. <bold>Objectives:</bold> Identify emphysema-associated biological pathways through transcriptomic analysis of bulk lung tissue, determine the cell types in which these emphysema-associated pathways are altered, and detect unique and overlapping transcriptomic signatures in blood and lung. <bold>Methods:</bold> Using RNA-seq data from 446 samples in the Lung Tissue Research Consortium (LTRC) and 3,606 blood samples from the COPDGene study, we examined the transcriptomic features of CT-quantified emphysema. We also leveraged publicly available lung single-cell RNA-seq data to identify cell types showing COPD-associated differential expression of the emphysema pathways found in the bulk analyses. <bold>Results:</bold> In the bulk lung RNA-seq analysis, 1,087 differentially expressed genes and 34 dysregulated pathways were significantly associated with emphysema. We observed alternative splicing of several genes and increased activity in pluripotency and cell barrier function pathways. Lung tissue and blood samples shared 361 differentially expressed genes and 3 biological pathways. Multiple lung cell types displayed dysregulation of epithelial barrier function pathways, and an imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages was detected. <bold>Conclusion:</bold> This study identified emphysema-related changes in gene expression and alternative splicing, cell-type specific dysregulated pathways, and instances of shared pathway dysregulation between blood and lung. These insights may aid in developing non-invasive screening methods and therapies for emphysema.