Bodas Manish, Vij Neeraj
Department of Medicine, University of Oklahoma, Oklahoma City, OK, United States.
Department of Pediatric Pulmonary Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Front Pharmacol. 2019 Feb 1;10:20. doi: 10.3389/fphar.2019.00020. eCollection 2019.
Cystic fibrosis (CF), a fatal genetic disorder predominant in the Caucasian population, is caused by mutations in the cystic fibrosis transmembrane conductance regulator () gene. The most common mutation is the deletion of phenylalanine from the position-508 (F508del-CFTR), resulting in a misfolded-CFTR protein, which is unable to fold, traffic and retain its plasma membrane (PM) localization. The resulting CFTR dysfunction, dysregulates variety of key cellular mechanisms such as chloride ion transport, airway surface liquid (ASL) homeostasis, mucociliary-clearance, inflammatory-oxidative signaling, and proteostasis that includes ubiquitin-proteasome system (UPS) and autophagy. A collective dysregulation of these key homoeostatic mechanisms contributes to the development of chronic obstructive cystic fibrosis lung disease, instead of the classical belief focused exclusively on ion-transport defect. Hence, therapeutic intervention(s) aimed at rescuing chronic CF lung disease needs to correct underlying defect that mediates homeostatic dysfunctions and not just chloride ion transport. Since targeting all the myriad defects individually could be quite challenging, it will be prudent to identify a process which controls almost all disease-promoting processes in the CF airways including underlying CFTR dysfunction. There is emerging experimental and clinical evidence that supports the notion that impaired cellular proteostasis and autophagy plays a central role in regulating pathogenesis of chronic CF lung disease. Thus, correcting the underlying proteostasis and autophagy defect in controlling CF pulmonary disease, primarily correcting the protein processing defect of F508del-CFTR protein has emerged as a novel intervention strategy. Hence, we discuss here both the rationale and significant therapeutic utility of emerging proteostasis and autophagy modulating drugs/compounds in controlling chronic CF lung disease, where targeted delivery is a critical factor-influencing efficacy.
囊性纤维化（CF）是一种主要在白种人群中出现的致命性遗传疾病，由囊性纤维化跨膜传导调节因子（CFTR）基因突变引起。最常见的突变是第508位苯丙氨酸缺失（F508del-CFTR），导致CFTR蛋白错误折叠，无法折叠、运输并保留其质膜（PM）定位。由此产生的CFTR功能障碍会失调多种关键细胞机制，如氯离子运输、气道表面液体（ASL）稳态、黏液纤毛清除、炎症氧化信号传导以及包括泛素-蛋白酶体系统（UPS）和自噬在内的蛋白质稳态。这些关键稳态机制的共同失调导致了慢性阻塞性囊性纤维化肺病的发展，而非传统观念中仅关注离子转运缺陷。因此，旨在挽救慢性CF肺病的治疗干预需要纠正介导稳态功能障碍的潜在缺陷，而不仅仅是氯离子运输。由于单独针对所有众多缺陷颇具挑战性，谨慎的做法是确定一个控制CF气道中几乎所有促病过程（包括潜在的CFTR功能障碍）的过程。越来越多的实验和临床证据支持这样一种观点，即细胞蛋白质稳态和自噬受损在慢性CF肺病发病机制调节中起核心作用。因此，纠正控制CF肺病中潜在的蛋白质稳态和自噬缺陷，主要是纠正F508del-CFTR蛋白的蛋白质加工缺陷，已成为一种新的干预策略。因此，我们在此讨论新兴的蛋白质稳态和自噬调节药物/化合物在控制慢性CF肺病中的原理和显著治疗效用，其中靶向递送是影响疗效的关键因素。
