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An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions

Abstract : Chronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality. Genome-wide Association Studies identified a locus including a nonsynonymous single nucleotide polymorphism in CHRNA5, rs16969968, encoding the nicotinic acetylcholine receptor α5 subunit, predisposing to both smoking and Chronic Obstructive Pulmonary Disease. Here we report that nasal polyps from rs16969968 non-smoking carriers exhibit airway epithelium remodeling and inflammation. These hallmarks of Chronic Obstructive Pulmonary Disease occur spontaneously in mice expressing human rs16969968. They are significantly amplified after exposure to porcine pancreatic elastase, an emphysema model, and to oxidative stress with a polymorphism-dependent alteration of lung function. Targeted rs16969968 expression in epithelial cells leads to airway remodeling in vivo, increased proliferation and production of pro-inflammatory cytokines through decreased calcium entry and increased adenylyl-cyclase activity. We show that rs16969968 directly contributes to Chronic Obstructive Pulmonary Disease-like lesions, sensitizing the lung to the action of oxidative stress and injury, and represents a therapeutic target.
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Submitted on : Thursday, November 4, 2021 - 12:51:27 PM
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Julie Routhier, Stéphanie Pons, Mohamed Freidja, Véronique Dalstein, Jérôme Cutrona, et al.. An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions. Nature Communications, Nature Publishing Group, 2021, 12, pp.6384. ⟨10.1038/s41467-021-26637-6⟩. ⟨pasteur-03414373⟩

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