An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions.
Julie RouthierStéphanie PonsMohamed Lamine FreidjaVéronique DalsteinJérôme CutronaAntoine JonquetNathalie LalunJean-Claude MérolMark LathropJerry A StitzelGwenola KervoazeMuriel PichavantPhilippe GossetJean-Marie TournierPhilippe BirembautValérian DormoyUwe MaskosPublished in: Nature communications (2021)
Chronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality. Genome-wide Association Studies identified a locus including a non-synonymous 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.
Keyphrases
- chronic obstructive pulmonary disease
- lung function
- oxidative stress
- endothelial cells
- cystic fibrosis
- air pollution
- smoking cessation
- genome wide association
- dna damage
- immune response
- ischemia reperfusion injury
- long non coding rna
- induced pluripotent stem cells
- binding protein
- chronic rhinosinusitis
- idiopathic pulmonary fibrosis
- anti inflammatory
- insulin resistance
- genome wide association study