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.

译文

囊性纤维化 (CF) 是一种以上皮细胞Cl-转运缺陷为特征的遗传性疾病,通过慢性炎症和氧化应激损害肺部。谷胱甘肽是上皮肺衬里液中的主要抗氧化剂,由于谷胱甘肽外排减少 (Gao L,Kim KJ,Yankaskas JR和Forman HJ. Am J Physiol肺细胞Mol Physiol 277: L113-L118,1999),在CF气道上皮的顶端液中减少。本研究研究了恢复氯化物运输是否也会恢复谷胱甘肽分泌的问题。我们发现形成Cl通道的肽 (N-K4-M2GlyR) 和K通道激活剂 (氯唑沙宗) 增加了Cl分泌,以布美他尼敏感的短路电流测量,并通过高效液相色谱法测量谷胱甘肽外排,在人CF气道上皮细胞系 (CFT1) 中。单独添加肽增加谷胱甘肽分泌 (对照值的181 +/- 8%),而单独的氯唑沙宗不显著影响谷胱甘肽外排; 然而,氯唑沙宗增强了肽对谷胱甘肽释放的作用 (对照值的359 +/- 16%)。这些研究表明,谷胱甘肽的外排与顶端氯化物的分泌有关,而与CF跨膜电导调节剂本身无关,并且可以从药理学上克服CF中谷胱甘肽外排的缺陷。

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