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

Dupin, Isabelle; Dubreuil, Marielle; Freund-Michel, Véronique; Maurat, Élise; Campagnac, Marilyne; Ousova, Olga; Trian, Thomas; Girodet, Pierre‐Olivier; Berger, Patrick

doi:10.1183/23120541.lungscienceconference-2019.pp225

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“…Using transgenic mice Dupin et al CXCR4 blockade alleviates pulmonary and cardiac outcomes in young COPD 6 deficient for CXCR4 or the CXCR4 antagonist plerixafor, we showed that lungs were protected against CS-induced both lung function alteration and fibrocytes accumulation, and that the right heart was resistant to cardiac remodelling. Some of these findings have been previously reported in abstract form [13,14].…”

Section: Introductionsupporting

confidence: 67%

“… Footnote Some of the results of this study have been previously reported in the form of an abstract (37, 38). …”

mentioning

confidence: 87%

“…O, P, Representative stainings of CXCL12 (magenta) and nucleus (blue) in peri-bronchial areas of mouse (O) and human (P) lungs. Lower panels: higher Footnote: Some of the results of this study have been previously reported in the form of an abstract (37,38).…”

mentioning

confidence: 90%

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CXCR4 blockade alleviates pulmonary and cardiac outcomes in early COPD

Dupin

Henrot

Maurat

et al. 2023

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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.

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Section: Introductionsupporting

confidence: 67%

“… Footnote Some of the results of this study have been previously reported in the form of an abstract (37, 38). …”

mentioning

confidence: 87%