Smith J J, Karp P H, Welsh M J
Department of Pediatrics, University of Iowa College of Medicine, Iowa City 52242.
J Clin Invest. 1994 Mar;93(3):1307-11. doi: 10.1172/JCI117087.
Cystic fibrosis (CF) airway epithelia exhibit defective transepithelial electrolyte transport: cAMP-stimulated Cl- secretion is abolished because of the loss of apical membrane cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels, and amiloride-sensitive Na+ absorption is increased two- to threefold because of increased amiloride-sensitive apical Na+ permeability. These abnormalities are thought to alter respiratory tract fluid, thereby contributing to airway disease, the major source of mortality in this genetic disease. However, the underlying hypothesis, that fluid transport is abnormal in CF airway epithelia, has not been tested. Most conjecture about fluid transport is based on measurements of Na+ and Cl- transport performed under short circuit conditions in Ussing chambers. But such studies differ from in vivo conditions in that transepithelial voltage and mucosal fluid composition are held constant. Therefore, we measured fluid transport and mucosal electrolyte composition in primary cultures of CF airway epithelia without holding transepithelial voltage and ion concentration gradients at zero. In normal epithelia, cAMP agonists plus amiloride stimulated NaCl and fluid secretion. In CF epithelia, cAMP agonists failed to stimulate fluid or electrolyte secretion, changes consistent with the loss of CFTR Cl- channels. But in striking contrast to predictions based on Ussing chamber studies, CF epithelia absorbed fluid at a rate no greater than normal epithelia. Moreover, amiloride, which inhibits Na+ channels, failed to inhibit fluid absorption by CF epithelia. These results have important implications for understanding the pathogenesis of CF airway disease and for the design and evaluation of therapy.
囊性纤维化（CF）气道上皮细胞表现出跨上皮电解质转运缺陷：由于顶端膜囊性纤维化跨膜传导调节因子（CFTR）氯离子通道缺失，cAMP刺激的氯离子分泌被消除，并且由于顶端对氨氯地平敏感的钠离子通透性增加，氨氯地平敏感的钠离子吸收增加了两到三倍。这些异常被认为会改变呼吸道液体，从而导致气道疾病，而气道疾病是这种遗传病的主要死亡原因。然而，CF气道上皮细胞中液体转运异常这一潜在假设尚未得到验证。大多数关于液体转运的推测是基于在尤斯灌流小室短路条件下进行的钠离子和氯离子转运测量。但此类研究与体内情况不同，因为跨上皮电压和黏膜液体成分保持恒定。因此，我们在不将跨上皮电压和离子浓度梯度维持在零的情况下，测量了CF气道上皮细胞原代培养物中的液体转运和黏膜电解质成分。在正常上皮细胞中，cAMP激动剂加氨氯地平刺激氯化钠和液体分泌。在CF上皮细胞中，cAMP激动剂未能刺激液体或电解质分泌，这些变化与CFTR氯离子通道缺失一致。但与基于尤斯灌流小室研究的预测形成鲜明对比的是，CF上皮细胞吸收液体的速率不高于正常上皮细胞。此外，抑制钠离子通道的氨氯地平未能抑制CF上皮细胞的液体吸收。这些结果对于理解CF气道疾病的发病机制以及治疗方案的设计和评估具有重要意义。
