Background: Macrophages and monocytes orchestrate the inflammatory processes in lungs. However, their role in the pathogenesis of chronic obstructive pulmonary disease (COPD), an inflammatory condition, is not well known. Here, we determined the characteristics of these cells in lungs of COPD patients and identified novel therapeutic targets.

Methods: We analyzed RNA sequencing (scRNA-seq) data of explanted human lung tissue from COPD (n=18) and control (n=28) lungs and found 16 transcriptomically distinct groups of macrophages and monocytes. We performed pathway and gene enrichment analyses to determine the characteristics of macrophages and monocytes from COPD (versus control) lungs and identify therapeutic targets, which were then validated using data from a randomized controlled trial of COPD patients (DISARM).

Results: Among alveolar macrophages, 176 genes were differentially expressed (83 up- and 93 down-regulated; Padj<0.05, |log2FC|>0.5) were enriched in downstream biological processes predicted to cause poor lipid uptake, and impaired cell activation, movement, and angiogenesis in COPD versus control lungs. Classical monocytes from COPD lungs harbored a differential geneset predicted to cause cell activation, mobilization, recruitment and a hyperinflammatory responses to influenza. In silico, fluticasone propionate was one of the top compounds to modulate the abnormal transcriptional profiles of these cells. In vivo, fluticasone/salmeterol combination significantly modulated the gene expression profiles of BAL cells of COPD patients (p < 0.05)

Conclusions: COPD lungs harbor transcriptionally distinct lung macrophages and monocytes, reflective of a dysfunctional and hyperinflammatory state. Inhaled corticosteroids and other compounds can modulate the transcriptomic profile of these cells in patients with COPD.

Keyword:

Macrophages, Monocytes, COPD, single cell RNA sequencing, fluticasone, drug discovery

Yushan Hu is a graduate student at Uvic, Department of Mathematics and Statistics. Bachelor’s degree in Computer Science and Technology from Northwestern Polytechnical University.

Her research interests include (1) Bioinformatics, (2) Biostatistics, (3) COPD, and (4) Big data problems.