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In addition to clinical methodologies, subtyping COPD has also been challenged by the reliance on human lung samples from late-stage diseases. Different COPD phenotypes may be initiated from the susceptibility of different cell types to cigarette smoke, environmental pollution, and infections at early stages that ultimately converge at later stages in airway remodeling and destruction of the alveoli when the disease is diagnosed. This perspective provides discussion points on how studies to date define different cell types of the lung that can initiate COPD pathogenesis, focusing on the susceptibility of macrophages, T and B cells, mast cells, dendritic cells, endothelial cells, and airway epithelial cells. Additional cell types, including fibroblasts, smooth muscle cells, neuronal cells, and other rare cell types not covered here, may also play a role in orchestrating COPD. Here, we discuss current knowledge gaps, such as which cell types drive distinct disease phenotypes and\/or stages of the disease and which cells are primarily affected by the genetic variants identified by whole genome-wide association studies. Applying new technologies that interrogate the functional role of a specific cell type or a combination of cell types as well as single-cell transcriptomics and proteomic approaches are creating new opportunities to understand and clarify the pathophysiology and thereby the clinical heterogeneity of COPD.<\/jats:p>","DOI":"10.1165\/rcmb.2023-0175ps","type":"journal-article","created":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T10:44:42Z","timestamp":1692182682000},"page":"500-507","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":14,"title":["Does Chronic Obstructive Pulmonary Disease Originate from Different Cell Types?"],"prefix":"10.1093","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3997-5839","authenticated-orcid":false,"given":"Yohannes","family":"Tesfaigzi","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L.","family":"Curtis","sequence":"additional","affiliation":[{"name":"Medical Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan"},{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1094-2600","authenticated-orcid":false,"given":"Irina","family":"Petrache","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Critical Care and Sleep Medicine, National Jewish Health, Denver, Colorado"},{"name":"University of Colorado, Denver, Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9686-5698","authenticated-orcid":false,"given":"Francesca","family":"Polverino","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, College of Medicine, Baylor University, Houston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farrah","family":"Kheradmand","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, College of Medicine, Baylor University, Houston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2101-8843","authenticated-orcid":false,"given":"Ian M.","family":"Adcock","sequence":"additional","affiliation":[{"name":"Department of Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen I.","family":"Rennard","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,11,1]]},"reference":[{"key":"2026012204062720800_bib1","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1136\/thoraxjnl-2016-209846","article-title":"Do COPD subtypes really exist? 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