Clunes Lucy A, McMillan-Castanares Naia, Mehta Neil, Mesadieu Afia, Rodriguez Jorge, Maj Mary, Clunes Mark T
Department of Pharmacology, St. George's University, Grenada, West Indies.
Medical Student Research Institute, St. George's University, Grenada, West Indies.
SAGE Open Med. 2020 Jun 25;8:2050312120933807. doi: 10.1177/2050312120933807. eCollection 2020.
Cystic fibrosis patients display multi-organ system dysfunction (e.g. pancreas, gastrointestinal tract, and lung) with pathogenesis linked to a failure of Cl secretion from the epithelial surfaces of these organs. If unmanaged, organ dysfunction starts early and patients experience chronic respiratory infection with reduced lung function and a failure to thrive due to gastrointestinal malabsorption. Early mortality is typically caused by respiratory failure. In the past 40 years of newborn screening and improved disease management have driven the median survival up from the mid-teens to 43-53, with most of that improvement coming from earlier and more aggressive management of the symptoms. In the last decade, promising pharmacotherapies have been developed for the correction of the underlying epithelial dysfunction, namely, Cl secretion. A new generation of systemic drugs target the mutated Cl channels in cystic fibrosis patients and allow trafficking of the immature mutated protein to the cell membrane (correctors), restore function to the channel once in situ (potentiators), or increase protein levels in the cells (amplifiers). Restoration of channel function prior to symptom development has the potential to significantly change the trajectory of disease progression and their evidence suggests that a modest restoration of Cl secretion may delay disease progression by decades. In this article, we review epithelial vectorial ion and fluid transport, its quantification and measurement as a marker for cystic fibrosis ion transport dysfunction, and highlight some of the recent therapies targeted at the dysfunctional ion transport of cystic fibrosis.
囊性纤维化患者表现出多器官系统功能障碍（如胰腺、胃肠道和肺部），其发病机制与这些器官上皮表面氯离子分泌功能衰竭有关。如果不加以治疗，器官功能障碍会早期出现，患者会经历慢性呼吸道感染，肺功能下降，并因胃肠道吸收不良而发育不良。早期死亡通常由呼吸衰竭引起。在过去40年中，新生儿筛查和疾病管理的改善使中位生存期从十几岁提高到了43 - 53岁，其中大部分改善来自于对症状的更早、更积极的管理。在过去十年中，已经开发出了有前景的药物疗法来纠正潜在的上皮功能障碍，即氯离子分泌。新一代全身性药物针对囊性纤维化患者中发生突变的氯离子通道，使未成熟的突变蛋白转运到细胞膜（校正剂），一旦在原位恢复通道功能（增强剂），或增加细胞中的蛋白水平（放大器）。在症状出现之前恢复通道功能有可能显著改变疾病进展轨迹，并且有证据表明，氯离子分泌的适度恢复可能使疾病进展延迟数十年。在本文中，我们综述上皮向量离子和液体转运、其作为囊性纤维化离子转运功能障碍标志物的量化和测量，并重点介绍一些针对囊性纤维化功能失调离子转运的最新疗法。
