Lung Transcriptomics Link Emphysema to Barrier Dysfunction and Macrophage Subpopulations.

Area of Science:

• Pulmonary Medicine
• Genomics
• Transcriptomics

Background:

• Emphysema pathogenesis and gene regulatory processes remain poorly understood.
• Efficient screening methods and disease-modifying therapies for emphysema are challenging to develop.
• Transcriptomic insights into emphysema may facilitate therapeutic and diagnostic advancements.

Purpose of the Study:

• Identify emphysema-associated biological pathways via bulk lung tissue transcriptomic analysis.
• Determine specific lung cell types exhibiting altered emphysema-associated pathways.
• Detect unique and overlapping transcriptomic signatures in both blood and lung samples.

Main Methods:

• RNA-sequencing data from 446 Lung Tissue Research Consortium (LTRC) lung samples and 3,606 COPDGene blood samples were analyzed.
• Chest computed tomography-quantified emphysema was correlated with transcriptomic features.
• Publicly available single-cell RNA-sequencing data were used to identify cell-type specific pathway alterations.

Main Results:

• 1,087 differentially expressed genes and 34 dysregulated pathways were significantly associated with emphysema in lung tissue.
• Alternative splicing and increased activity in pluripotency and cell barrier pathways were observed.
• Shared differentially expressed genes and pathways were identified between lung and blood samples; epithelial barrier pathways were dysregulated across multiple lung cell types, with distinct activities in macrophage subpopulations.

Conclusions:

• Emphysema is associated with significant changes in gene expression and alternative splicing.
• Cell-type specific pathway dysregulation, particularly in epithelial barrier function and macrophage subpopulations, was identified.
• Shared transcriptomic signatures between blood and lung indicate potential for non-invasive biomarkers.