期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 101, 期 10, 页码 3691-3696出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0308393100
关键词
ascorbate; Cl channel opener; epithelia; Delta F508 CFTR; airway disease
资金
- NHLBI NIH HHS [HL-071829, R01 HL071829] Funding Source: Medline
Vitamin C (L-ascorbate) is present in the respiratory lining fluid of human lungs, and local deficits occur during oxidative stress. Here we report a unique function of vitamin C on the cystic fibrosis (CF) transmembrane conductance regulator (CFTR), a cAMP-dependent Cl channel that regulates epithelial surface fluid secretion. Vitamin C (100 muM) induced the openings of CFTR Cl channels by increasing its average open probability from 0 to 0.21 +/- 0.08, without a detectable increase in intracellular cAMP levels. Exposure of the apical airway surface to vitamin C stimulated the transepithelial Cl secretion to 68% of forskolin-stimulated currents. The average half-maximal stimulatory constant was 36.5 +/- 2.9 muM, which corresponds to physiological concentrations. When vitamin C was instilled into the nasal epithelium of human subjects, it effectively activated Cl transport in vivo. In CF epithelia, previous treatment of the underlying trafficking defect with trimethylamine oxide or expression of WT CFTR restored the activation of Cl transport by vitamin C. Sodium dependency and phloretin sensitivity, as well as the expression of transcripts for sodium-dependent vitamin C transporter (SVCT)-1 and SVCT2, support a model in which an apical vitamin C transporter is central for relaying the effect of vitamin C to CFTR. We conclude that cellular vitamin C is a biological regulator of CFTR-mediated Cl secretion in epithelia. The pool of vitamin C in the respiratory tract represents a potential nutraceutical and pharmaceutical target for the complementary treatment of sticky airway secretions by enhancing epithelial fluid secretion.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据