ABSTRACT
Rationale Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease lacking effective treatment. Focusing on the early stage of COPD should help to discover disease modifying therapies.
Objectives In this study, we examined the role of the CXCL12/CXCR4 axis in both a mouse model of early COPD and in human samples from COPD patients.
Methods To generate the early COPD model, mice were exposed to cigarette smoke (CS) for 10 weeks and intranasal instillations of polyinosinic–polycytidylic acid (poly(I:C)) for 5 weeks to mimic exacerbations.
Measurements and Main Results Exposed mice presented mild airway obstruction, peri-bronchial fibrosis and right heart remodeling. CXCR4 expressing cells number was increased in the blood of exposed mice, as well as in the blood of patients with COPD. Lung CXCL12 expression was higher in both exposed mice and early COPD patients. 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 remodeling. CXCR4-/- and plerixafor-treated mice also had less CXCR4-expressing circulating cells and a lower density of peri-bronchial fibrocytes.
Conclusions 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 within a drug repurposing approach.
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, Roche, Chiesi, Novartis and Legs Poix fundation. 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, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Sanofi, personal fees from Menarini, personal fees from TEVA, outside the submitted work; in addition, PB 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). All other authors declare they have no competing interests.
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
- LLN
- Lower limit of normal
- 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
