Targeting CXCR4 as a therapeutic strategy to improve outcomes in a mouse model of early chronic obstructive pulmonary disease (COPD)

The chemokine receptor CXCR4 is an attractive therapeutic target for COPD treatment because it participates to pathologic process such as vascularization, inflammation and remodeling, in part by mediating migration of cells, including fibrocytes. Fibrocytes, a rare population of fibroblast-like cells produced by the bone marrow stroma, are assumed to play a key role in COPD. Targeting CXCR4 to limit the recruitment of fibrocytes during exacerbations could be of potential interest, but preclinical evidences supporting a beneficial role of CXCR4 antagonists for COPD treatment are lacking. While exposing mice to cigarette smoke during 10 weeks and intranasal instillation of poly-IC to mimick exacerbations, we created experimental conditions in which functional obstruction appears in about 70% of exposed mice. Right heart remodeling, quantified by Fulton index, also occurs in exposed mice. One day after the last poly-IC challenge, both the levels of circulating fibrocytes and lung CXCL12  are higher in exposed mice. Remarkably, the level of cells co-expressing CD45 and a-smooth muscle actin that probably represent differentiated fibrocytes, is increased in the lungs of exposed mice and is positively associated to lung functional obstruction. Targeting CXCR4 with daily injections of plerixafor (AMD3100) during the 5 last weeks of the protocole improves lung function, decrases cardiac remodeling without altering cell inflammation in the broncho alveolar lavage fluid. Our results thus indicate that plerixafor has beneficial effects in animal model of COPD, and provide a framework to translate preclinical findings to clinical settings.