CXCR4 blockade alleviates pulmonary and cardiac outcomes in young COPD

Abstract

ABSTRACTBackgroundChronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease lacking effective treatment. Focusing on young COPD should help to discover disease modifying therapies. We aimed to examine the role of the CXCL12/CXCR4 axis in young COPD from both human samples and murine models.MethodsBlood samples and lung tissues of young COPD patients and controls were obtained in order to analyse CXCL12 and CXCR4 levels. To generate a young COPD model, ten-week-old 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.ResultsCXCR4 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 young 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 exposed 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 remodelling. CXCR4-/-and plerixafor-treated mice also had less CXCR4-expressing circulating cells and a lower density of peri-bronchial fibrocytes.ConclusionWe demonstrate that targeting CXCR4 has beneficial effects in an animal model of young COPD and provide a framework to translate these preclinical findings to clinical settings in a drug repurposing approach.What is already known on this topicWhereas the CXCL12/CXCR4 axis has already been identified in COPD pathophysiology, preclinical evidences supporting a beneficial role of CXCR4 antagonists for COPD treatment are lacking.What this study addsCXCL12 and CXCR4 are upregulated in the lung and in the blood of patients with young COPD, respectively. Genetic and pharmacological inhibition of CXCR4 in experimental young COPD mice model reduces the number of CXCR4-expressing cells in the peripheral circulation and fibrocyte recruitment into the lungs, along with a proteomic signature consistent with a decrease of inflammation. Overall, it improves lung function and cardiac tissue remodelling.How this study might affect research, practice or policyCXCR4 inhibitors may be therapeutically exploited to slow down the progression of young COPD.