Tildy Bernadett E, Rogers Duncan F
Imperial College London, Imperial College London, London, UK.
Pharmacology. 2015;95(3-4):117-32. doi: 10.1159/000377638. Epub 2015 Mar 19.
In cystic fibrosis (CF), genetic mutations in the CF transmembrane conductance regulator (CFTR) gene cause reduced chloride efflux from ciliated airway epithelial cells. This results in a reduction in periciliary liquid (PCL) depth of the airway surface liquid due to associated reduced water efflux. PCL layer dehydration reduces mucociliary clearance (MCC), leading to airway obstruction (reduced airflow and inflammation due to pathogen invasion) with mucus plug formation.
Rehydrating mucus increases MCC. Mucus hydration can be achieved by direct hydration (administering osmotic agents to set up an osmotic gradient), using CFTR modulators to correct dysfunctional CFTR, or it can be achieved pharmacologically (targeting other ion channels on airway epithelial cells). Key Messages: The molecular mechanisms of several therapies are discussed in the context of pre-clinical and clinical trial studies. Currently, only the osmotic agent 7% hypertonic saline and the CFTR 'potentiator' VX-770 (ivacaftor) are used clinically to hydrate mucus. Emerging therapies include the osmotic agent mannitol (Bronchitol), the intracellular Ca(2+)-raising agent Moli1901/lancovutide, the CFTR potentiator sildenafil [phosphodiesterase type 5 (PDE5) inhibitor] and the CFTR 'corrector' VX-809 (lumacaftor). Other CFTR correctors (e.g. 'chemical chaperones') are also showing pre-clinical promise.
在囊性纤维化（CF）中，CF跨膜传导调节因子（CFTR）基因的基因突变导致纤毛气道上皮细胞中氯离子外流减少。这导致气道表面液体的纤毛周围液体（PCL）深度降低，原因是相关的水外流减少。PCL层脱水会降低黏液纤毛清除率（MCC），导致气道阻塞（由于病原体入侵导致气流减少和炎症）并形成黏液栓。
使黏液再水化可增加MCC。黏液水化可通过直接水化（给予渗透剂以建立渗透梯度）、使用CFTR调节剂纠正功能失调的CFTR来实现，也可通过药理学方法（靶向气道上皮细胞上的其他离子通道）来实现。关键信息：在临床前和临床试验研究的背景下讨论了几种治疗方法的分子机制。目前，临床上仅使用渗透剂7%高渗盐水和CFTR“增强剂”VX-770（依伐卡托）来使黏液水化。新兴的治疗方法包括渗透剂甘露醇（支气管醇）、细胞内钙离子升高剂Moli1901/兰考韦肽、CFTR增强剂西地那非[5型磷酸二酯酶（PDE5）抑制剂]和CFTR“校正剂”VX-809（鲁马卡托）。其他CFTR校正剂（如“化学伴侣”）也显示出临床前的应用前景。
