Synthetic chloride channel restores glutathione secretion in cystic fibrosis airway epithelia

Cystic fibrosis (CF), an inherited disease characterized by defective epith elial Cl- transport, damages lungs via chronic inflammation and oxidative s tress. Glutathione, a major antioxidant in the epithelial lung lining fluid , is decreased in the apical fluid of CF airway epithelia due to reduced gl utathione efflux (Gao L, Kim KJ, Yankaskas JR, and Forman HJ. Am J Physiol Lung Cell Mol Physiol 277: L113-L118, 1999). The present study examined the question of whether restoration of chloride transport would also restore g lutathione secretion. We found that a Cl- channel-forming peptide (N-K-4-M2 GlyR) and a K+ channel activator (chlorzoxazone) increased Cl- secretion, m easured as bumetanide-sensitive short-circuit current, and glutathione effl ux, measured by high-performance liquid chromatography, in a human CF airwa y epithelial cell line (CFT1). Addition of the peptide alone increased glut athione secretion (181 +/- 8% of the control value), whereas chlorzoxazone alone did not significantly affect glutathione efflux; however, chlorzoxazo ne potentiated the effect of the peptide on glutathione release (359 +/- 16 % of the control value). These studies demonstrate that glutathione efflux is associated with apical chloride secretion, not with the CF transmembrane conductance regulator per se, and the defect of glutathione efflux in CF c an be overcome pharmacologically.