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Oxidant stress stimulates anion secretion from the human airway epithelial cell line calu‐3: implications for cystic fibrosis lung disease
Author(s) -
Cowley Elizabeth A.,
Linsdell Paul
Publication year - 2002
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2002.022400
Subject(s) - cystic fibrosis transmembrane conductance regulator , forskolin , apical membrane , dids , chloride channel , cystic fibrosis , secretion , chemistry , epithelial polarity , medicine , endocrinology , microbiology and biotechnology , biology , stimulation , biochemistry , cell , membrane
Exposure to reactive oxygen species (ROS) is associated with tissue damage in the lung and may be a common element in the pathogenesis of all inflammatory lung diseases. Exposure to the ROS hydrogen peroxide (H 2 O 2 ) evoked a rapid increase in transepithelial anion secretion across monolayers of the human submucosal gland serous cell line Calu‐3. This increase was almost entirely abolished by the addition of diphenylamine‐2‐carboxylate (DPC), implicating the cystic fibrosis transmembrane conductance regulator (CFTR) Cl − channel in the response. The response was also reduced by inhibitors of basolateral K + channels. Studies of electrically isolated apical and basolateral membranes revealed that H 2 O 2 stimulated both apical Cl − and basolateral K + conductances ( G Cl and G K ). Apical G Cl was sensitive to DPC, but unaffected by 4,4′‐diisothiocyanatostilbene‐2,2′‐disulfonic acid (DIDS), suggesting that CFTR is the major anion conduction pathway mediating the response to H 2 O 2 . Additionally, H 2 O 2 had no effect on G Cl in the presence of the adenylate cyclase inhibitor SQ22536 or following maximal stimulation of G Cl with forskolin, implicating the cAMP‐dependent protein kinase pathway in the apical response to H 2 O 2 . Basolateral G K was reduced by the K + channel inhibitors clotrimazole and clofilium, indicating roles for KCNN4 and KCNQ1 in the H 2 O 2 ‐stimulated response. We propose that ROS‐stimulated anion secretion from serous cells plays an important role in keeping the airways clear from damaging radicals that could potentially initiate tissue destruction. Our finding that this response is CFTR dependent suggests that an important host defence mechanism would be dysfunctional in the cystic fibrosis (CF) lung. Loss of this compensatory protective mechanism could expose the CF lung to ROS for extended periods, which could be important in the pathogenesis of CF lung disease.