Rationale: While many studies have examined gene expression in lung tissue, the gene regulatory processes underlying emphysema are still not well understood. Finding efficient non-imaging screening methods and disease-modifying therapies has been challenging, but knowledge of the transcriptomic features of emphysema may help in this effort. Objectives: Our goals were to identify emphysema-associated biological pathways through transcriptomic analysis of bulk lung tissue, to determine the lung cell types in which these emphysema-associated pathways are altered, and to detect unique and overlapping transcriptomic signatures in blood and lung. Methods: Using RNA-sequencing data from 456 samples in the Lung Tissue Research Consortium and 2,370 blood samples from the COPDGene study, we examined the transcriptomic features of computed tomography quantified emphysema. We also queried lung single-cell RNA-sequencing data to identify cell types showing COPD-associated differential expression of the emphysema pathways found in the bulk analyses. Measurements and Main Results: In the lung, 1,055 differentially expressed genes and 29 dysregulated pathways were significantly associated with emphysema. We observed alternative splicing of genes regulating NF-κB and cell adhesion and increased activity in the TGF-β and FoxO signaling 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. Lung tissue and blood samples shared 251 differentially expressed genes and two pathways (oxidative phosphorylation and ribosomal function). Conclusions: 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.

The authors have declared no competing interest.

This work was supported by NHLBI K08HL141601, K08HL146972, K08HL136928, K01HL157613, R01HL124233, U01 HL089897, R01 HL147326, and U01 HL089856. The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.

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