CXCR4 blockade alleviates pulmonary and cardiac outcomes in early COPD

Abstract

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease lacking effective treatment. Focusing on early COPD should help to discover disease modifying therapies. We aimed to examine the role of the CXCL12/CXCR4 axis in early COPD from both human samples and murine models. Blood samples and lung tissues of early COPD patients and controls were obtained in order to analyse CXCL12 and CXCR4 levels. To generate an early COPD model, ten-week-old male C57BL/6J mice were exposed to cigarette smoke (CS) for 10 weeks and intranasal instillations of polyinosinic-polycytidylic acid (poly(I:C)) for the last 5 weeks to mimic exacerbations. CXCR4 expressing cells number was increased in the blood of patients with COPD, as well as in the blood of exposed mice. Lung CXCL12 expression was higher in both early COPD patients and exposed mice. Exposed mice presented mild airway obstruction, peri-bronchial fibrosis and right heart thickening. The density of fibrocytes expressing CXCR4 was increased in the bronchial submucosa of these mice. Conditional inactivation of CXCR4 at adult stage as well as pharmacological inhibition of CXCR4 with plerixafor injections improved lung function, reduced inflammation, and protected against CS and poly-(I:C)-induced airway and cardiac remodeling. CXCR4-/- and plerixafor-treated mice also had less CXCR4-expressing circulating cells and a lower density of peri-bronchial fibrocytes. We demonstrate that targeting CXCR4 has beneficial effects in an animal model of early COPD and provide a framework to translate these preclinical findings to clinical settings in a drug repurposing approach. Clinical relevanceWe demonstrate that CXCL12/CXCR4 axis plays an important role in the pathogenesis of early COPD. Inhibition of this axis improves lung function and cardiac tissue remodeling, supporting the future use of CXCR4 inhibitors to slow down the progression of the disease.