a Marsico Lung Institute , University of North Carolina , Chapel Hill , NC , USA.
b Department of Cell Biology & Physiology , University of North Carolina , Chapel Hill , NC , USA.
Expert Opin Ther Targets. 2018 Aug;22(8):687-701. doi: 10.1080/14728222.2018.1501361. Epub 2018 Jul 26.
Cystic fibrosis is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for the CFTR anion channel. In the absence of functional CFTR, the epithelial Na channel is also dysregulated. Airway surface liquid (ASL) hydration is maintained by a balance between epithelial sodium channel (ENaC)-led Na absorption and CFTR-dependent anion secretion. This finely tuned homeostatic mechanism is required to maintain sufficient airway hydration to permit the efficient mucus clearance necessary for a sterile lung environment. In CF airways, the lack of CFTR and increased ENaC activity lead to ASL/mucus dehydration that causes mucus obstruction, neutrophilic infiltration, and chronic bacterial infection. Rehydration of ASL/mucus in CF airways can be achieved by inhibiting Na absorption with pharmacological inhibitors of ENaC. Areas covered: In this review, we discuss ENaC structure and function and its role in CF lung disease and focus on ENaC inhibition as a potential therapeutic target to rehydrate CF mucus. We also discuss the failure of the first generation of pharmacological inhibitors of ENaC and recent alternate strategies to attenuate ENaC activity in the CF lung. Expert opinion: ENaC is an attractive therapeutic target to rehydrate CF ASL that may serve as a monotherapy or function in parallel with other treatments. Given the increased number of strategies being employed to inhibit ENaC, this is an exciting and optimistic time to be in this field.
囊性纤维化是一种常染色体隐性遗传病，由囊性纤维化跨膜电导调节因子（CFTR）基因突变引起，该基因编码 CFTR 阴离子通道。在缺乏功能性 CFTR 的情况下，上皮钠通道也会失调。气道表面液体（ASL）的水合作用通过上皮钠通道（ENaC）介导的 Na 吸收和 CFTR 依赖性阴离子分泌之间的平衡来维持。这种精细的动态平衡机制是维持足够的气道水合作用以允许无菌肺环境中有效清除黏液所必需的。在 CF 气道中，CFTR 的缺乏和 ENaC 活性的增加导致 ASL/黏液脱水，导致黏液阻塞、嗜中性粒细胞浸润和慢性细菌感染。CF 气道中的 ASL/黏液再水合可以通过抑制 ENaC 的药理学抑制剂来实现。涵盖领域：在这篇综述中，我们讨论了 ENaC 的结构和功能及其在 CF 肺部疾病中的作用，并重点讨论了 ENaC 抑制作为一种潜在的治疗靶点，以重新水化 CF 黏液。我们还讨论了第一代 ENaC 药理学抑制剂的失败以及最近用于减轻 CF 肺部 ENaC 活性的替代策略。专家意见：ENaC 是一种有吸引力的治疗靶点，可以重新水化 CF ASL，可以作为单一疗法或与其他治疗方法并行发挥作用。鉴于抑制 ENaC 的策略数量不断增加，这是一个令人兴奋和乐观的领域。
