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

Fibrocytes, a rare population of fibroblast-like cells of hematopoietic origin, are assumed to play a key role in COPD. Targeting the CXCL12-CXCR4 axis to limit the recruitment of fibrocytes into the lungs could be of potential interest, but preclinical evidences supporting a beneficial role of CXCR4 antagonists for COPD treatment are lacking. By exposing mice to cigarette smoke (CS) during 10 weeks and intranasal instillations of poly-IC to mimick exacerbations, we created experimental conditions leading to airway obstruction, peribronchial fibrosis and right heart remodeling in exposed mice. The densities of fibrocytes in the bronchial submucosa and lung CXCL12 were found higher in exposed mice. Moreover, CXCR4 expression was increased in circulating cells of exposed mice, as well as in the blood of patients with COPD. Pharmacological inhibition of CXCR4 with plerixafor (AMD3100) injections and conditional inactivation of CXCR4 at adult stage both improved lung function and protected against CS-induced airway and cardiac remodeling. Plerixafor-treatred mice and CXCR4^−/− mice also had reduced levels of CXCR4 expression in circulating cells and a lower density of peribronchial fibrocytes. Our results thus indicate that plerixafor has beneficial effects in an animal model of COPD, and provide a framework to translate preclinical findings to clinical settings.