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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 the RNA sequencing (scRNA-seq) data of explanted human lung tissue from COPD (n = 18) and control (n = 28) lungs and found 16 transcriptionally 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 to identify the therapeutic targets, which were then validated using data from a randomized controlled trial of COPD patients (DISARM). Results: In the alveolar macrophages, 176 genes were differentially expressed (83 up- and 93 downregulated; Padj &lt; 0.05, |log2FC| &gt; 0.5) and 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 gene set predicted to cause the activation, mobilization, and recruitment of cells and a hyperinflammatory response to influenza. In silico, the corticosteroid fluticasone propionate was one of the top compounds predicted to modulate the abnormal transcriptional profiles of these cells. In vivo, a fluticasone\u2013salmeterol combination significantly modulated the gene expression profiles of bronchoalveolar lavage cells of COPD patients (p &lt; 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.<\/jats:p>","DOI":"10.3390\/cells12242771","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T08:09:17Z","timestamp":1701763757000},"page":"2771","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Single-Cell Sequencing of Lung Macrophages and Monocytes Reveals Novel Therapeutic Targets in COPD"],"prefix":"10.3390","volume":"12","author":[{"given":"Yushan","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Mathematics and Statistics, University of Victoria, Victoria, BC V8P 5C2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3044-621X","authenticated-orcid":false,"given":"Xiaojian","family":"Shao","sequence":"additional","affiliation":[{"name":"Digital Technologies Research Centre, National Research Council Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, University of Saskatchewan, Saskatoon, SK S7N 5A2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Li","sequence":"additional","affiliation":[{"name":"UBC Centre for Heart Lung Innovation, St. Paul\u2019s Hospital, Vancouver, BC V6Z 1Y6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey M.","family":"Nonis","sequence":"additional","affiliation":[{"name":"UBC Centre for Heart Lung Innovation, St. Paul\u2019s Hospital, Vancouver, BC V6Z 1Y6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme J.","family":"Koelwyn","sequence":"additional","affiliation":[{"name":"UBC Centre for Heart Lung Innovation, St. Paul\u2019s Hospital, Vancouver, BC V6Z 1Y6, Canada"},{"name":"Faculty of Health Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4728-2343","authenticated-orcid":false,"given":"Xuekui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, University of Victoria, Victoria, BC V8P 5C2, Canada"},{"name":"UBC Centre for Heart Lung Innovation, St. Paul\u2019s Hospital, Vancouver, BC V6Z 1Y6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0756-6643","authenticated-orcid":false,"given":"Don D.","family":"Sin","sequence":"additional","affiliation":[{"name":"UBC Centre for Heart Lung Innovation, St. Paul\u2019s Hospital, Vancouver, BC V6Z 1Y6, Canada"},{"name":"Division of Respirology, Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1900164","DOI":"10.1183\/13993003.00164-2019","article-title":"Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: The GOLD science committee report 2019","volume":"53","author":"Singh","year":"2019","journal-title":"Eur. 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