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Focusing on early COPD should help to discover disease modifying therapies. We examined the role of the CXCL12\/CXCR4 axis in early COPD using human samples and murine models. Blood samples and lung tissues from both individuals with early COPD and controls were analyzed for CXCL12 and CXCR4 levels. To generate an early-like COPD model, 10-week-old male C57BL\/6J mice were exposed to cigarette smoke for 10 weeks and intranasal instillations of polyinosinic\u2013polycytidylic acid (poly(I:C)) for the last 5 weeks to mimic exacerbations. The number of cells expressing CXCR4 was increased in the blood of individuals with COPD, as well as in the blood of exposed mice. Lung CXCL12 expression was higher in both patients with early COPD and exposed mice. Exposed mice presented mild airflow obstruction, peribronchial fibrosis, and right heart thickening. The density of fibrocyte-like cells expressing CXCR4 increased in the bronchial submucosa of these mice. Conditional inactivation of CXCR4, as well as pharmacological inhibition of CXCR4 with plerixafor injections, improved lung function, reduced inflammation, and protected against cigarette smoke and poly(I:C)-induced airway and cardiac remodeling. CXCR4\u2212\/\u2212-treated and plerixafor-treated mice also had fewer CXCR4-expressing circulating cells and a lower density of peribronchial fibrocyte-like cells. We demonstrate that targeting CXCR4 has beneficial effects in an animal model mimicking early COPD. Although these preclinical findings are encouraging, further research is needed to explore the potential for transferring these insights into clinical applications, including drug repurposing.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0303oc","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T14:50:21Z","timestamp":1744123821000},"page":"530-544","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":3,"title":["CXCR4 Blockade Alleviates Pulmonary and Cardiac Outcomes in Early Chronic Obstructive Pulmonary Disease"],"prefix":"10.1093","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4992-9625","authenticated-orcid":false,"given":"Isabelle","family":"Dupin","sequence":"first","affiliation":[{"name":"INSERM, CRCTB, U 1045, IHU Liryc, and"},{"name":"Institut universitaire de France, Paris, 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