ABSTRACT
Background Chronic 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.
Methods Blood 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.
Results 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 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.
Conclusion We 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 topic Whereas 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 adds CXCL12 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 policy CXCR4 inhibitors may be therapeutically exploited to slow down the progression of young COPD.
Competing Interest Statement
ID has 2 patents delivered (i) (EP 3050574 i.e., Use of plerixafor for treating and/or preventing acute exacerbations of chronic obstructive pulmonary disease); (ii) (EP 20173595.8 i.e., New compositions and methods of treating COVID-19 Disease). ID report a grant from the Fondation Bordeaux Universite, with funding from Assistance Ventilatoire a Domicile (AVAD) and Federation Girondine de Lutte contre les Maladies Respiratoires (FGLMR). PH reports non-financial support from AVAD and Chiesi, outside the submitted work and a grant from the Fondation Bordeaux Universite, with funding from AVAD and FGLMR. POG reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Chiesi, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sanofi, outside the submitted work. POG has 2 patents delivered (i) (EP 3050574 i.e., Use of plerixafor for treating and/or preventing acute exacerbations of chronic obstructive pulmonary disease); (ii) (EP 20173595.8 i.e., New compositions and methods of treating COVID-19 Disease). MZ reports personal fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Novartis, Chiesi, GlaxoSmithKline and non-financial support Lilly outside the submitted work and a grant from the Fondation Bordeaux Universite, with funding from AVAD and FGLMR. PB is the medical coordinator of the French national cohort (i.e., COBRA), which received grants from AstraZeneca, GlaxoSmithKine, and Chiesi. Moreover, PB reports grants and personal fees from Novartis, personal fees and non-financial support from Chiesi, grants, personal fees and non-financial support from Boehringer Ingelheim, grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from GSK, personal fees and non-financial support from Sanofi, personal fees from Menarini, personal fees from TEVA, outside the submitted work; in addition, PB has 4 patents delivered (i) (EP 3050574 i.e., Use of plerixafor for treating and/or preventing acute exacerbations of chronic obstructive pulmonary disease); (ii) (EP 20173595.8 i.e., New compositions and methods of treating COVID-19 Disease); (iii) (WO2017203064A1 i.e., MRI Method for the geometrical characterization of pulmonary airways); (iv) (WO2021018439A1 i.e., Method for generating a biomarker system). All other authors declare they have no competing interests.
Footnotes
This version of the manuscript has been revised to include novel quantification of CXCL12 stainings and to improve data presentation.
Abbreviations
- BAL
- Broncho-alveolar lavage
- bFGF
- basic Fibroblast Growth Factor
- BSM
- Bronchial smooth muscle
- CS
- Cigarette smoke
- CT
- Computed tomographic
- ECG
- Electrocardiogram
- FEV1
- Forced expiratory volume in 1 second
- FEV0.05
- Forced expiratory volume in 0.05 second
- FVC
- Forced vital capacity
- IFN
- Interferon
- LV + S
- Left ventricle plus septum
- MRI
- Magnetic Resonance Imaging
- Poly-(I:C)
- Polyinosinic–polycytidylic acid
- RA
- Room air
- RV
- Right ventricle
- RVSP
- Right ventricular systolic pressure
- VEGF
- Vascular Endothelial Growth Factor
