Bronchial epithelial calcium metabolism impairment in smokers and chronic obstructive pulmonary disease

Abstract

The airway epithelium represents a fragile environmental interface potentially disturbed by cigarette smoke (CS), the major risk factor for developing chronic obstructive pulmonary disease (COPD). CS leads to bronchial epithelial damage on ciliated, goblet, and club cells, which could involve calcium (Ca21) signaling. Ca21 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 Ca21 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 Ca21 signaling. First, we showed that the endoplasmic reticulum (ER) depletion of Ca21 stores was decreased in patients with COPD and that the Ca21 influx was decreased in epithelial cells from smokers (regardless of COPD status). In addition, acute CS exposure led to a decrease in ER Ca21 release, significant in smoker subjects, and to a decrease in Ca21 influx only in control subjects. Furthermore, the differential expression of 55 genes involved in Ca21 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 Ca21 influx and ciliary beating, but not mucus and cytokine secretion or epithelial repair, in control subjects. Our data suggest that Ca21 signaling is impaired in smoker epithelia (regardless of COPD status) and involves Orai3. Moreover, Orai3 is additionally involved in ciliary beating.