Istituto di Biomembrane, Bioenergetica e Biotecnologie Molecolari (IBIOM) - CNR, Via G. Amendola 165/A, 70126, Bari, Italy.
Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica - Università di Bari, Via E. Orabona 4, 70126, Bari, Italy.
J Bioenerg Biomembr. 2018 Apr;50(2):117-129. doi: 10.1007/s10863-018-9748-x. Epub 2018 Mar 9.
Cystic fibrosis (CF) is associated to impaired Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel also causing decreased glutathione (GSH) secretion, defective airway bacterial clearance and inflammation. Here we checked the main ROS-producing and ROS-scavenging enzymes as potential additional factors involved in CF pathogenesis. We found that CFBE41o-cells, expressing F508del CFTR, have increased NADPH oxidase (NOX) activity and expression level, mainly responsible of the increased ROS production, and decreased glutathione reductase (GR) activity, not dependent on GR protein level decrease. Furthermore, defective CFTR proved to cause both extracellular and intracellular GSH level decrease, probably by reducing the amount of extracellular GSH-derived cysteine required for cytosolic GSH synthesis. Importantly, we provide evidence that defective CFTR and NOX/GR activity imbalance both contribute to NADPH and GSH level decrease and ROS overproduction in CF cells.
囊性纤维化（CF）与囊性纤维化跨膜电导调节因子（CFTR）通道功能障碍有关，也会导致谷胱甘肽（GSH）分泌减少、气道细菌清除和炎症功能缺陷。在这里，我们检查了主要的活性氧（ROS）产生和清除酶，作为可能参与 CF 发病机制的额外因素。我们发现，表达 F508del CFTR 的 CFBE41o-细胞具有增加的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（NOX）活性和表达水平，主要负责增加 ROS 的产生，以及减少谷胱甘肽还原酶（GR）活性，但不依赖于 GR 蛋白水平的降低。此外，有缺陷的 CFTR 被证明会导致细胞外和细胞内 GSH 水平降低，可能是通过减少细胞内 GSH 合成所需的细胞外 GSH 衍生半胱氨酸的量。重要的是，我们提供的证据表明，有缺陷的 CFTR 和 NOX/GR 活性失衡都会导致 NADPH 和 GSH 水平降低以及 CF 细胞中 ROS 的过度产生。
