Division of Pulmonary Medicine, Department of Pediatrics, and.
Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
JCI Insight. 2018 Feb 22;3(4). doi: 10.1172/jci.insight.93029.
Traditional pulmonary therapies for cystic fibrosis (CF) target the downstream effects of CF transmembrane conductance regulator (CFTR) dysfunction (the cause of CF). Use of one such therapy, β-adrenergic bronchodilators (such as albuterol), is nearly universal for airway clearance. Conversely, novel modulator therapies restore function to select mutant CFTR proteins, offering a disease-modifying treatment. Recent trials of modulators targeting F508del-CFTR, the most common CFTR mutation, suggest that chronic β-agonist use may undermine clinical modulator benefits. We therefore sought to understand the impact of chronic or excess β-agonist exposure on CFTR activation in human airway epithelium. The present studies demonstrate a greater than 60% reduction in both wild-type and modulator-corrected F508del-CFTR activation following chronic exposure to short- and long-acting β-agonists. This reduction was due to reduced cellular generation of cAMP downstream of the β-2 adrenergic receptor-G protein complex. Our results point towards a posttranscriptional reduction in adenylyl cyclase function as the mechanism of impaired CFTR activation produced by prolonged β-agonist exposure. β-Agonist-induced CFTR dysfunction was sufficient to abrogate VX809/VX770 modulation of F508del-CFTR in vitro. Understanding the clinical relevance of our observations is critical for CF patients using these drugs, and for investigators to inform future CFTR modulator drug trials.
传统的囊性纤维化（CF）肺部治疗方法针对 CF 跨膜电导调节因子（CFTR）功能障碍的下游效应（CF 的病因）。β-肾上腺素能支气管扩张剂（如沙丁胺醇）等一种这样的治疗方法几乎普遍用于气道清除。相反，新型调节剂治疗方法可恢复某些突变 CFTR 蛋白的功能，提供一种疾病修饰治疗。最近针对 F508del-CFTR 的调节剂试验表明，慢性β激动剂的使用可能会破坏临床调节剂的疗效。因此，我们试图了解慢性或过量β激动剂暴露对人类气道上皮 CFTR 激活的影响。本研究表明，在长期暴露于短效和长效β-激动剂后，野生型和调节剂校正的 F508del-CFTR 的激活均减少了 60%以上。这种减少是由于β-2 肾上腺素能受体-G 蛋白复合物下游的细胞 cAMP 生成减少所致。我们的结果表明，延长β-激动剂暴露会导致腺苷酸环化酶功能的转录后减少，从而导致 CFTR 激活受损。β-激动剂诱导的 CFTR 功能障碍足以使 VX809/VX770 对 F508del-CFTR 的调节在体外失效。了解我们观察结果的临床相关性对于使用这些药物的 CF 患者以及研究人员告知未来 CFTR 调节剂药物试验至关重要。
