Department of Biology, University of North Carolina at Pembroke, Pembroke, NC 28372;
Marsico Lung Institute/University of North Carolina Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):E7272-E7281. doi: 10.1073/pnas.1617383114. Epub 2017 Aug 14.
Mucociliary clearance is composed of three components (i.e., mucin secretion, airway surface hydration, and ciliary-activity) which function coordinately to clear inhaled microbes and other foreign particles from airway surfaces. Airway surface hydration is maintained by water fluxes driven predominantly by active chloride and sodium ion transport. The ion channels that mediate electrogenic ion transport are regulated by extracellular purinergic signals that signal through G protein-coupled receptors. These purinoreceptors and the signaling pathways they activate have been identified as possible therapeutic targets for treating lung disease. A systems-level description of airway surface liquid (ASL) homeostasis could accelerate development of such therapies. Accordingly, we developed a mathematical model to describe the dynamic coupling of ion and water transport to extracellular purinergic signaling. We trained our model from steady-state and time-dependent experimental measurements made using normal and cystic fibrosis (CF) cultured human airway epithelium. To reproduce CF conditions, reduced chloride secretion, increased potassium secretion, and increased sodium absorption were required. The model accurately predicted ASL height under basal normal and CF conditions and the collapse of surface hydration due to the accelerated nucleotide metabolism associated with CF exacerbations. Finally, the model predicted a therapeutic strategy to deliver nucleotide receptor agonists to effectively rehydrate the ASL of CF airways.
黏液纤毛清除由三个组成部分组成（即粘蛋白分泌、气道表面水合和纤毛活性），它们协同作用以清除气道表面上吸入的微生物和其他外来颗粒。气道表面水合作用由主要由活性氯离子和钠离子转运驱动的水通量维持。介导电致离子转运的离子通道受通过 G 蛋白偶联受体信号传递的细胞外嘌呤能信号调节。这些嘌呤能受体及其激活的信号通路已被确定为治疗肺部疾病的潜在治疗靶点。对气道表面液（ASL）动态平衡的系统级描述可以加速此类疗法的开发。因此，我们开发了一个数学模型来描述离子和水转运与细胞外嘌呤能信号之间的动态耦合。我们使用正常和囊性纤维化（CF）培养的人气道上皮细胞的稳态和时变实验测量值对模型进行了训练。为了模拟 CF 条件，需要减少氯离子分泌、增加钾离子分泌和增加钠离子吸收。该模型准确预测了正常和 CF 条件下的 ASL 高度以及与 CF 恶化相关的加速核苷酸代谢导致的表面水合作用崩溃。最后，该模型预测了一种治疗策略，即用核苷酸受体激动剂有效重新水化 CF 气道的 ASL。
