Mall M, Bleich M, Kuehr J, Brandis M, Greger R, Kunzelmann K
University Children's Hospital, Albert-Ludwigs-University Freiburg, 79106 Freiburg, Germany.
Am J Physiol. 1999 Sep;277(3):G709-16. doi: 10.1152/ajpgi.1999.277.3.G709.
Cystic fibrosis (CF) patients show characteristic defects in epithelial ion transport, such as failure in cAMP-dependent Cl- secretion. Because the cystic fibrosis transmembrane conductance regulator (CFTR) also functions as a downregulator of epithelial Na+ channels (ENaC), enhanced Na+ conductance was found in the airways of CF patients. Here, we examined whether enhanced epithelial Na+ conductance is also present in the colonic epithelium of CF patients and examined the underlying mechanisms. Thus transepithelial voltages were measured, and equivalent short-circuit currents (I(sc-eq)) were determined by means of a novel type of Ussing chamber. Non-CF tissues demonstrated cAMP-dependent Cl- secretion that was absent in biopsies of CF patients. Correspondingly, Isc-eq was inhibited in non-CF but not in CF epithelia when synthesis of endogenous prostaglandins was blocked by indomethacin. In the presence of indomethacin, a larger portion of amiloride-sensitive Isc-eq was detected in CF tissues, suggesting enhanced ENaC conductance in colonic mucosa of CF patients. Increase of intracellular cAMP by forskolin and IBMX inhibited amiloride-sensitive ENaC currents in non-CF tissues but not in CF biopsies. Therefore, enhanced epithelial Na+ conductance is present in the CF colon and is probably due to missing downregulation by CFTR.
囊性纤维化（CF）患者上皮离子转运存在特征性缺陷，如cAMP依赖性Cl⁻分泌功能障碍。由于囊性纤维化跨膜传导调节因子（CFTR）也作为上皮钠通道（ENaC）的下调因子发挥作用，因此在CF患者气道中发现Na⁺电导增强。在此，我们研究了CF患者结肠上皮中是否也存在增强的上皮Na⁺电导，并探讨了其潜在机制。因此，我们测量了跨上皮电压，并通过一种新型的尤斯灌流小室测定了等效短路电流（I(sc-eq)）。非CF组织表现出cAMP依赖性Cl⁻分泌，而CF患者活检组织中则不存在这种分泌。相应地，当内源性前列腺素的合成被吲哚美辛阻断时，Isc-eq在非CF上皮中受到抑制，但在CF上皮中未受抑制。在存在吲哚美辛的情况下，在CF组织中检测到更大比例的amiloride敏感Isc-eq，这表明CF患者结肠黏膜中ENaC电导增强。福斯可林和IBMX增加细胞内cAMP可抑制非CF组织中amiloride敏感的ENaC电流，但对CF活检组织无效。因此，CF结肠中存在增强的上皮Na⁺电导，这可能是由于CFTR下调缺失所致。
