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Oxidant stress stimulates anion secretion from the human airway epithelial cell line Calu-3: implications for cystic fibrosis lung disease

Elizabeth A. Cowley and Paul Linsdell

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 (H₂O₂) 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 H₂O₂ 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 H₂O₂. Additionally, H₂O₂ 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 H₂O₂. Basolateral G_K was reduced by the K⁺ channel inhibitors clotrimazole and clofilium, indicating roles for KCNN4 and KCNQ1 in the H₂O₂-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.

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