Pseudomonas aeruginosa inhibits endocytic recycling of CFTR in polarized human airway epithelial cells
Pseudomonas aeruginosa inhibits endocytic recycling of CFTR in polarized human airway epithelial cells
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DOI：
10.1152/ajpcell.00108.2005
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发表时间：
2006-03-01
影响因子：
5.5
通讯作者：
Stanton, BA
中科院分区：
文献类型：
--
作者：
Swiatecka-Urban, A;Moreau-Marquis, S;Stanton, BA
囊性纤维化（CF）患者CFTR基因中最常见的突变Delta F508导致顶端质膜中CFTR C1（-）通道的缺失，这反过来又导致粘膜纤毛清除功能受损，这是抵御吸入细菌的第一道防线。铜绿假单胞菌在定殖和慢性感染肺部方面特别成功，并且是CF患者中大多数发病率和死亡率的原因。通过降低温度或化学手段拯救Delta F508-CFTR揭示了该蛋白质至少部分作为Cl（-）通道起作用。因此，目前的研究工作集中在鉴定恢复顶膜中CFTR的存在以减轻CF症状的药物。由于对铜绿假单胞菌对顶膜中CFTR的影响知之甚少，因此铜绿假单胞菌是否会影响旨在恢复CFTR质膜表达的新药的疗效尚不清楚。因此，本研究的目的是确定铜绿假单胞菌是否影响极化的人气道上皮细胞中CFTR介导的C1（-）分泌。我们在此报道，铜绿假单胞菌的无细胞滤液通过抑制CFTR的内吞再循环，从而抑制极化的人气道上皮细胞中顶端膜中WT-CFTR和Delta F508-CFTR C1（-）通道的数量，减少CFTR介导的跨上皮C1（-）分泌。这些数据表明，铜绿假单胞菌的慢性感染可能干扰旨在增加Delta F508-CFTR的顶膜表达的治疗策略。
The most common mutation in the CFTR gene in individuals with cystic fibrosis (CF), Delta F508, leads to the absence of CFTR C1(-) channels in the apical plasma membrane, which in turn results in impairment of mucociliary clearance, the first line of defense against inhaled bacteria. Pseudomonas aeruginosa is particularly successful at colonizing and chronically infecting the lungs and is responsible for the majority of morbidity and mortality in patients with CF. Rescue of Delta F508-CFTR by reduced temperature or chemical means reveals that the protein is at least partially functional as a C1(-) channel. Thus current research efforts have focused on identification of drugs that restore the presence of CFTR in the apical membrane to alleviate the symptoms of CF. Because little is known about the effects of P. aeruginosa on CFTR in the apical membrane, whether P. aeruginosa will affect the efficacy of new drugs designed to restore the plasma membrane expression of CFTR is unknown. Accordingly, the objective of the present study was to determine whether P. aeruginosa affects CFTR-mediated C1(-) secretion in polarized human airway epithelial cells. We report herein that a cell-free filtrate of P. aeruginosa reduced CFTR-mediated transepithelial C1(-) secretion by inhibiting the endocytic recycling of CFTR and thus the number of WT-CFTR and Delta F508-CFTR C1(-) channels in the apical membrane in polarized human airway epithelial cells. These data suggest that chronic infection with P. aeruginosa may interfere with therapeutic strategies aimed at increasing the apical membrane expression of Delta F508-CFTR.