Mall Marcus A
Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Germany.
Exp Physiol. 2009 Feb;94(2):171-4. doi: 10.1113/expphysiol.2008.042994. Epub 2008 Dec 5.
Increased airway Na(+) absorption mediated by the amiloride-sensitive epithelial Na(+) channel (ENaC) is a basic defect in cystic fibrosis (CF) lung disease. Cystic fibrosis is one of the most common lethal hereditary diseases and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR acts as a cAMP-dependent Cl(-) channel and regulator of ENaC, and CFTR dysfunction causes impaired Cl(-) secretion and increased Na(+) absorption in the airways of CF patients. Evidence from in vitro studies suggested that increased Na(+) absorption produces airway surface liquid (ASL) volume depletion and led to the generation of transgenic mice with airway-specific overexpression of ENaC to elucidate the role of this mechanism in the in vivo pathogenesis of lung disease. Studies of the pulmonary phenotype of betaENaC-overexpressing mice demonstrated that increased airway Na(+) absorption caused ASL depletion and reduced mucus transport, producing a CF-like lung disease with airway mucus plugging, chronic airway inflammation and pulmonary mortality. Further, recent pharmacological studies demonstrated that preventive, but not late, inhibition of increased airway Na(+) absorption with the ENaC blocker amiloride reduced morbidity and mortality in this murine model of CF lung disease. These results support a critical role of ENaC in the in vivo pathogenesis of CF lung disease and suggest that amiloride may be an effective preventive therapy for CF patients.
由氨氯地平敏感的上皮钠通道（ENaC）介导的气道钠（Na⁺）吸收增加是囊性纤维化（CF）肺部疾病的一个基本缺陷。囊性纤维化是最常见的致死性遗传性疾病之一，由囊性纤维化跨膜传导调节因子（CFTR）基因突变引起。CFTR作为一种依赖cAMP的氯离子（Cl⁻）通道和ENaC的调节因子，CFTR功能障碍导致CF患者气道中Cl⁻分泌受损和Na⁺吸收增加。体外研究证据表明，Na⁺吸收增加会导致气道表面液体（ASL）量减少，并促使人们培育出气道特异性过表达ENaC的转基因小鼠，以阐明该机制在肺部疾病体内发病机制中的作用。对过表达βENaC小鼠的肺部表型研究表明，气道Na⁺吸收增加会导致ASL减少和黏液转运降低，产生一种类似CF的肺部疾病，伴有气道黏液阻塞、慢性气道炎症和肺部死亡率增加。此外，最近的药理学研究表明，在这种CF肺部疾病小鼠模型中，用ENaC阻滞剂氨氯地平预防性（而非晚期）抑制气道Na⁺吸收增加可降低发病率和死亡率。这些结果支持ENaC在CF肺部疾病体内发病机制中起关键作用，并表明氨氯地平可能是CF患者的一种有效预防性治疗药物。
