Improvement of defective cystic fibrosis airway epithelial wound repair after CFTR rescue
Improvement of defective cystic fibrosis airway epithelial wound repair after CFTR rescue
复制标题
DOI：
10.1183/09031936.00221711
复制
发表时间：
2012-12-01
影响因子：
24.3
通讯作者：
Brochiero, Emmanuelle
中科院分区：
文献类型：
--
作者：
Nguyen Thu Ngan Trinh;Bardou, Olivier;Brochiero, Emmanuelle
气道损伤和重塑是囊性纤维化（CF）肺部病理进展的重要组成部分。尽管修复机制致力于恢复上皮完整性，但这些过程显然不足以维持 CF 气道中的肺功能。因此，我们的目的是研究基本囊性纤维化跨膜电导调节器 (CFTR) 缺陷如何影响上皮伤口愈合，并确定 CFTR 校正是否可以改善伤口愈合。进行伤口愈合实验以及细胞迁移和增殖测定，以研究人类 CF 和非 CF 气道细胞的上皮修复的早期阶段。在非 CF 细胞中使用 CFTR 小干扰 (si)RNA 和抑制剂 GlyH101 评估 CFTR 功能，在 CF 细胞中使用 CFTR 校正器 VRT-325 进行 CFTR 救援后进行相反的评估。 伤口愈合实验首先表明，CF 患者的气道细胞修复速度慢于非 CF 细胞。非 CF 主气道细胞中的 CFTR 抑制或沉默显着抑制伤口闭合。 GlyH101 还降低细胞迁移和增殖。有趣的是，CF气道细胞系中的野生型CFTR转导或CFBE-AF508和原发性CF支气管单层中的VRT-325校正显着改善了伤口愈合。总之，我们的结果表明功能性CFTR在伤口修复中发挥着关键作用，CFTR校正可能代表了促进CF气道修复过程的新策略。
Airway damage and remodelling are important components of lung pathology progression in cystic fibrosis (CF). Although repair mechanisms are engaged to restore the epithelial integrity, these processes are obviously insufficient to maintain lung function in CF airways. Our aims were therefore to study how the basic cystic fibrosis transmembrane conductance regulator (CFTR) defect could impact epithelial wound healing and to determine if CFTR correction could improve it.Wound-healing experiments, as well as cell migration and proliferation assays, were performed to study the early phases of epithelial repair in human CF and non-CF airway cells. CFTR function was evaluated using CFTR small interferring (si)RNA and inhibitor GlyH101 in non-CF cells, and conversely after CFTR rescue with the CFTR corrector VRT-325 in CF cells.Wound-healing experiments first showed that airway cells from CF patients repaired slower than non-CF cells. CFTR inhibition or silencing in non-CF primary airway cells significantly inhibited wound closure. GlyH101 also decreased cell migration and proliferation. Interestingly, wild-type CFTR transduction in CF airway cell lines or CFTR correction with VRT-325 in CFBE-AF508 and primary CF bronchial monolayers significantly improved wound healing.Altogether our results demonstrated that functional CFTR plays a critical role in wound repair, and CFTR correction may represent a novel strategy to promote the airway repair processes in CF.