Marsico Lung Institute, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Int J Mol Sci. 2022 Sep 6;23(18):10232. doi: 10.3390/ijms231810232.
Mucociliary clearance is a critical defense mechanism for the lungs governed by regionally coordinated epithelial cellular activities, including mucin secretion, cilia beating, and transepithelial ion transport. Cystic fibrosis (CF), an autosomal genetic disorder caused by the dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, is characterized by failed mucociliary clearance due to abnormal mucus biophysical properties. In recent years, with the development of highly effective modulator therapies, the quality of life of a significant number of people living with CF has greatly improved; however, further understanding the cellular biology relevant to CFTR and airway mucus biochemical interactions are necessary to develop novel therapies aimed at restoring gene expression in the lungs. In this article, we discuss recent advances of transcriptome analysis at single-cell levels that revealed a heretofore unanticipated close relationship between secretory MUC5AC and MUC5B mucins and CFTR in the lungs. In addition, we review recent findings on airway mucus biochemical and biophysical properties, focusing on how mucin secretion and CFTR-mediated ion transport are integrated to maintain airway mucus homeostasis in health and how CFTR dysfunction and restoration of function affect mucus properties.
黏液清除是肺部的一种重要防御机制，受区域协调的上皮细胞活动调控，包括粘蛋白分泌、纤毛摆动和跨上皮离子转运。囊性纤维化（CF）是一种常染色体遗传疾病，由囊性纤维化跨膜电导调节因子（CFTR）通道功能障碍引起，其特征是由于异常的黏液生物物理特性而导致黏液清除失败。近年来，随着高效调节剂治疗的发展，许多 CF 患者的生活质量得到了极大改善；然而，为了开发旨在恢复肺部基因表达的新型治疗方法，进一步了解与 CFTR 和气道黏液生化相互作用相关的细胞生物学是必要的。本文讨论了单细胞水平转录组分析的最新进展，这些进展揭示了肺部中分泌型 MUC5AC 和 MUC5B 粘蛋白与 CFTR 之间迄今尚未预料到的密切关系。此外，我们还回顾了气道黏液生化和生物物理特性的最新发现，重点讨论了粘蛋白分泌和 CFTR 介导的离子转运如何整合以维持健康状态下气道黏液的动态平衡，以及 CFTR 功能障碍和功能恢复如何影响黏液特性。
