Turner Mark J, Matthes Elizabeth, Billet Arnaud, Ferguson Amy J, Thomas David Y, Randell Scott H, Ostrowski Lawrence E, Abbott-Banner Kathy, Hanrahan John W
Department of Physiology, McIntyre Medical Sciences Building, McGill University, Montreal, Canada; McGill CF Translational Research Centre, Montreal, Canada;
Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina;
Am J Physiol Lung Cell Mol Physiol. 2016 Jan 1;310(1):L59-70. doi: 10.1152/ajplung.00324.2015. Epub 2015 Nov 6.
Cystic fibrosis (CF), a genetic disease caused by mutations in the CFTR gene, is a life-limiting disease characterized by chronic bacterial airway infection and severe inflammation. Some CFTR mutants have reduced responsiveness to cAMP/PKA signaling; hence, pharmacological agents that elevate intracellular cAMP are potentially useful for the treatment of CF. By inhibiting cAMP breakdown, phosphodiesterase (PDE) inhibitors stimulate CFTR in vitro and in vivo. Here, we demonstrate that PDE inhibition by RPL554, a drug that has been shown to cause bronchodilation in asthma and chronic obstructive pulmonary disease (COPD) patients, stimulates CFTR-dependent ion secretion across bronchial epithelial cells isolated from patients carrying the R117H/F508del CF genotype. RPL554-induced CFTR activity was further increased by the potentiator VX-770, suggesting an additional benefit by the drug combination. RPL554 also increased cilia beat frequency in primary human bronchial epithelial cells. The results indicate RPL554 may increase mucociliary clearance through stimulation of CFTR and increasing ciliary beat frequency and thus could provide a novel therapeutic option for CF.
囊性纤维化（CF）是一种由CFTR基因突变引起的遗传性疾病，是一种危及生命的疾病，其特征为慢性细菌性气道感染和严重炎症。一些CFTR突变体对cAMP/PKA信号的反应性降低；因此，提高细胞内cAMP水平的药物可能对CF治疗有用。通过抑制cAMP分解，磷酸二酯酶（PDE）抑制剂在体外和体内均可刺激CFTR。在此，我们证明，RPL554（一种已被证明可使哮喘和慢性阻塞性肺疾病（COPD）患者支气管扩张的药物）对PDE的抑制作用，可刺激携带R117H/F508del CF基因型患者分离出的支气管上皮细胞进行CFTR依赖性离子分泌。增效剂VX-770可进一步增强RPL554诱导的CFTR活性，表明该药物组合具有额外益处。RPL554还可增加原代人支气管上皮细胞的纤毛摆动频率。结果表明，RPL554可能通过刺激CFTR和增加纤毛摆动频率来增加黏液纤毛清除功能，从而可能为CF提供一种新的治疗选择。
