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Am J Physiol Lung Cell Mol Physiol 281: L24-L30, 2001;
1040-0605/01 $5.00
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Vol. 281, Issue 1, L24-L30, July 2001

SPECIAL TOPIC
Synthetic chloride channel restores glutathione secretion in cystic fibrosis airway epithelia

Lin Gao1, James R. Broughman2, Takeo Iwamoto2, John M. Tomich2, Charles J. Venglarik3, and Henry Jay Forman1

1 Department of Environmental Health Sciences and 3 Department of Physiology and Biophysics and Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama 35294; and 2 Department of Biochemistry, Kansas State University, Manhattan, Kansas 66506

Cystic fibrosis (CF), an inherited disease characterized by defective epithelial Cl- transport, damages lungs via chronic inflammation and oxidative stress. Glutathione, a major antioxidant in the epithelial lung lining fluid, is decreased in the apical fluid of CF airway epithelia due to reduced glutathione 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 glutathione secretion. We found that a Cl- channel-forming peptide (N-K4-M2GlyR) and a K+ channel activator (chlorzoxazone) increased Cl- secretion, measured as bumetanide-sensitive short-circuit current, and glutathione efflux, measured by high-performance liquid chromatography, in a human CF airway epithelial cell line (CFT1). Addition of the peptide alone increased glutathione secretion (181 ± 8% of the control value), whereas chlorzoxazone alone did not significantly affect glutathione efflux; however, chlorzoxazone 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 can be overcome pharmacologically.

chlorzoxazone; channel-forming peptide; glutathione transport; antioxidant


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