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Role of the Cystic Fibrosis Transmembrane Conductance Channel in Human Airway Smooth Muscle

¹ Seymour Heisler Laboratory of the Montreal Chest Institute and Meakins-Christie Laboratories, McGill University; ² Physiology Department, McGill University, Montreal, Quebec, Canada; and ³ University of Montreal Hospital Center, Montreal, Quebec, Canada

Correspondence and requests for reprints should be addressed to James G. Martin, M.D., D.Sc., Meakins Christie Laboratories, Department of Medicine, McGill University, 3626 St. Urbain, Montreal, PQ, H2X 2P2 Canada. E-mail: james.martin{at}mcgill.ca

Patients with cystic fibrosis (CF) suffer from asthma-like symptoms and gastrointestinal cramps, attributed to a mutation in the CF transmembrane conductance regulator (CFTR) gene present in a variety of cells. Pulmonary manifestations of the disease include the production of thickened mucus and symptoms of asthma, such as cough and wheezing. A possible alteration in airway smooth muscle (ASM) cell function of patients with CF has not been investigated. The aim of this study was to determine whether the (CFTR) channel is present and affects function of human ASM cells. Cell cultures were obtained from the main or lobar bronchi of patients with and without CF, and the presence of the CFTR channel detected by immunofluorescence. Cytosolic Ca²⁺ was measured using Fura-2 and dual-wavelength microfluorimetry. The results show that CFTR is expressed in airway bronchial tissue and in cultured ASM cells. Peak Ca²⁺ release in response to histamine was significantly decreased in CF cells compared with non-CF ASM cells (357 ± 53 nM versus 558 ± 20 nM; P < 0.001). The CFTR pharmacological blockers, glibenclamide and N-phenyl anthranilic acid, significantly reduced histamine-induced Ca²⁺ release in non-CF cells, and similar results were obtained when CFTR expression was varied using antisense oligonucleotides. In conclusion, these data show that the CFTR channel is present in ASM cells, and that it modulates the release of Ca²⁺ in response to contractile agents. In patients with CF, a dysfunctional CFTR channel could contribute to the asthma diathesis and gastrointestinal problems experienced by these patients.

Key Words: cystic fibrosis • histamine • chloride channel • glibenclamide • oligodeoxynucleotide

CLINICAL RELEVANCE This study shows that the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel is involved in the regulation of intracellular calcium in airway smooth muscle cells. Mutations in the CFTR channel may contribute to the asthma diathesis observed in patients with CF.

 

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