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Salmeterol Restores Secretory Functions in Cystic Fibrosis Airway Submucosal Gland Serous Cells

¹ INSERM, UMRS 926, Reims, France; ² Laboratoire de Microscopie Electronique Analytique, Université de Reims Champagne-Ardenne, Reims, France; ³ INSERM, UMRS 903, Reims, France; and ⁴ Laboratoire des Microscopies et Nanomatériaux, Université de Reims Champagne-Ardenne, Reims, France

Correspondence and requests for reprints should be addressed to Franck Delavoie, Ph.D., INSERM UMRS 926, Laboratoire de Microscopie Electronique Analytique, 21 rue Clément Ader, B.P. 138, 51685 Reims Cedex 2, France. E-mail: franck.delavoie{at}univ-reims.fr

The activity of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) can be mediated by surface G protein–coupled receptors such as the β₂-adrenergic receptor. In this study, we explored the effect of a long-acting β₂-adrenergic agonist, salmeterol, on the CFTR-dependent secretory capacity of a human CF tracheal gland serous cell line (CF-KM4), homozygous for the delF508 mutation. We showed that, compared with the untreated CF serous cells, a 24-hour pre-incubation period with 200 nM salmeterol induced an 83% increase in delF508-CFTR–mediated chloride efflux. The restoration of the bioelectric properties is associated with increased apical surface pool of delF508-CFTR. Salmeterol induced a decrease in ion concentration and an increase in the level of hydration of the mucus packaged inside the CF secretory granules. The effects of salmeterol are not associated with a persistent production of cAMP. Western blotting on isolated secretory granules demonstrated immunoreactivity for CFTR and lysozyme. In parallel, we measured by atomic force microscopy an increased size of secretory granules isolated from CF serous cells compared with non-CF serous cells (MM39 cell line) and showed that salmeterol was able to restore a CF cell granule size similar to that of non-CF cells. To demonstrate that the salmeterol effect was a CFTR-dependent mechanism, we showed that the incubation of salmeterol-treated CF serous cells with CFTR-inh172 suppressed the restoration of normal secretory functions. The capacity of salmeterol to restore the secretory capacity of glandular serous cells suggests that it could also improve the airway mucociliary clearance in patients with CF.

Key Words: submucosal gland serous cell • secretory granule • salmeterol • CFTR

CLINICAL RELEVANCE The capacity of salmeterol to restore the chloride secretion and mucus hydration in cystic fibrosis (CF) airway glandular cells reinforces the hypothesis that a long-acting β2-agonist is able to improve pulmonary function and respiratory symptoms in CF patients.

 

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