Centre for Mathematics and Physics in the Life Sciences and Experimental Biology, University College London, Gower Street, London, WC1E 6BT, United Kingdom.
J Physiol. 2013 Aug 1;591(15):3681-92. doi: 10.1113/jphysiol.2013.253955. Epub 2013 Jun 3.
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes an anion channel. In the human lung CFTR loss causes abnormal ion transport across airway epithelial cells. As a result CF individuals produce thick mucus, suffer persistent bacterial infections and have a much reduced life expectancy. Trans-epithelial potential difference (Vt) measurements are routinely carried out on nasal epithelia of CF patients in the clinic. CF epithelia exhibit a hyperpolarised basal Vt and a larger Vt change in response to amiloride (a blocker of the epithelial Na(+) channel, ENaC). Are these altered bioelectric properties solely a result of electrical coupling between the ENaC and CFTR currents, or are they due to an increased ENaC permeability associated with CFTR loss? To examine these issues we have developed a quantitative mathematical model of human nasal epithelial ion transport. We find that while the loss of CFTR permeability hyperpolarises Vt and also increases amiloride-sensitive Vt, these effects are too small to account for the magnitude of change observed in CF epithelia. Instead, a parallel increase in ENaC permeability is required to adequately fit observed experimental data. Our study provides quantitative predictions for the complex relationships between ionic permeabilities and nasal Vt, giving insights into the physiology of CF disease that have important implications for CF therapy.
囊性纤维化 (CF) 是由囊性纤维化跨膜电导调节因子 (CFTR) 基因突变引起的，该基因编码一种阴离子通道。在人类肺部，CFTR 的缺失导致气道上皮细胞的离子转运异常。因此，CF 个体产生浓稠的黏液，持续受到细菌感染，预期寿命大大缩短。临床上常规对 CF 患者的鼻上皮进行跨上皮电位差 (Vt) 测量。CF 上皮细胞表现出基础 Vt 的超极化和对阿米洛利（上皮钠离子通道，ENaC 的阻滞剂）的更大 Vt 变化。这些改变的生物电特性仅仅是 ENaC 和 CFTR 电流之间的电耦合的结果，还是由于与 CFTR 缺失相关的 ENaC 通透性增加所致？为了研究这些问题，我们开发了一个人类鼻上皮离子转运的定量数学模型。我们发现，尽管 CFTR 通透性的丧失会使 Vt 超极化，并且还会增加阿米洛利敏感的 Vt，但这些影响太小，无法解释 CF 上皮中观察到的变化幅度。相反，需要平行增加 ENaC 通透性才能充分拟合观察到的实验数据。我们的研究为离子通透性和鼻 Vt 之间的复杂关系提供了定量预测，深入了解了 CF 疾病的生理学，对 CF 治疗具有重要意义。
