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Am J Respir Cell Mol Biol. 2019 Apr 3. doi: 10.1165/rcmb.2018-0228OC. [Epub ahead of print]

Bronchial Epithelial Calcium Metabolism Impairment in Smokers and COPD: Decreased ORAI3 Signaling.

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CHRU Montpellier, Respiratory Disease Department, Montpellier, France ;
CHRU Montpellier, Respiratory Disease Department, Montpellier, France.
Inserm U1046, 352096, CNRS UMR 9214, PHYMEDEXP, Montpellier, Languedoc-Roussillon, France.
Centre Interdisciplinaire de Nanoscience de Marseille, 201019, Marseille, Provence-Alpes-Côte d'Azu, France.
Laboratoire Charles Coulomb (L2C), UMR 5221 CNRS-UM F34095, Montpellier, France.
Aix-Marseille University, APHM, CV2N, Inserm U1263 INRA 1260, Clinique des bronches allergies et sommeil, Marseille, France.
Centre Hospitalier Regional Universitaire de Montpellier, 26905, departement of medical information, Montpellier, Languedoc-Roussillon, France.
GlaxoSmithKline, Refractory Respiratory Inflammation DPU, Respiratory TAU, Stevenage, United Kingdom of Great Britain and Northern Ireland.


The airway epithelium represents a fragile environmental interface potentially disturbed by cigarette smoke, the major risk factor for developing Chronic Obstructive Pulmonary Disease (COPD). Cigarette smoke leads to bronchial epithelial damage on ciliated, goblet and club cells, which could involve calcium signaling. Calcium is a key messenger involved in virtually all fundamental physiological functions, including mucus and cytokine secretion, cilia beating and epithelial repair. In this study, we analyzed calcium signaling in Air-Liquid Interface reconstituted bronchial epithelium from control subjects and smokers (with and without COPD). We further aimed to determine how smoking impaired calcium signaling. Firstly, we showed that the endoplasmic reticulum (ER) depletion of calcium stores was decreased in COPD patients and that the calcium influx was decreased in epithelial cells from smokers (regardless of COPD status). In addition, acute cigarette smoke exposition lead to a decrease in ER calcium release, significant in smoker subjects, and to a decrease in calcium influx only in control subjects. Furthermore, the differential expression of 55 genes involved in calcium signaling highlighted that only ORAI3 expression was significantly altered in smokers (regardless of COPD status). Finally, we incubated epithelial cells with an ORAI antagonist (GSK-7975A). GSK-7975A altered calcium influx and ciliary beating but not mucus and cytokine secretion or epithelial repair in control subjects. Our data suggest that calcium signaling is impaired in smoker epithelia (regardless of COPD status) and involves ORAI3. Moreover, ORAI3 is additionally involved in ciliary beating.


ORAI3; bronchial epithelial cells; calcium signaling; cigarette smoke


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