Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration
Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration
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DOI：
10.1096/fj.11-192377
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发表时间：
2012-02-01
期刊：
影响因子：
4.8
通讯作者：
Tarran, Robert
中科院分区：
文献类型：
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作者：
Clunes, Lucy A.;Davies, Catrin M.;Tarran, Robert
香烟烟雾（CS）暴露会诱导黏液阻塞以及慢性支气管炎（CB）的发生。尽管许多此类反应是由基因决定的，但对于香烟烟雾在蛋白质水平上对肺上皮细胞的影响却知之甚少。因此，我们验证了香烟烟雾对囊性纤维化跨膜传导调节因子（CFTR）蛋白有直接影响这一假说，这种影响可能损害气道水化作用，导致囊性纤维化和慢性支气管炎所共有的黏液停滞特征。体内和体外研究表明，香烟烟雾迅速降低CFTR活性，导致气道表面液体（ASL）体积减少（即脱水）。进一步的研究显示，香烟烟雾诱导CFTR内化。令人惊讶的是，被香烟烟雾内化的CFTR并不与溶酶体蛋白共定位。相反，大部分CFTR转移到细胞内的抗洗涤剂组分中，并与中间丝波形蛋白共定位，这表明香烟烟雾诱导CFTR移动到一个类似聚集体的核周区室。为了测试气道脱水是否可以逆转，我们使用高渗盐水（HS）作为渗透剂来使ASL重新水化。高渗盐水恢复了暴露于香烟烟雾的脱水气道培养物中的ASL高度。同样，吸入高渗盐水恢复了慢性支气管炎患者的黏液运输并提高了清除率。因此，我们提出香烟烟雾暴露通过使CFTR内化迅速损害CFTR功能，导致ASL脱水，这促进了黏液停滞和黏液清除失败，使吸烟者有患慢性支气管炎的风险。此外，我们的数据表明，使气道表面重新水化的策略可能为慢性支气管炎患者提供一种新的治疗形式。 - 克卢内斯，L.A.，戴维斯，C.M.，科克利，R.D.，亚历山德罗夫，A.A.，亨德森，A.G.，泽曼，K.L.，沃辛顿，E.N.，根茨施，M.，克雷达，S.M.，乔隆，D.，贝内特，W.D.，赖尔登，J.R.，布歇，R.C.，塔兰，R. 香烟烟雾暴露诱导CFTR内化和不溶性，导致气道表面液体脱水。《美国实验生物学会联合会杂志》26，533 - 545（2012年）。www.fasebj.org
Cigarette smoke (CS) exposure induces mucus obstruction and the development of chronic bronchitis (CB). While many of these responses are determined genetically, little is known about the effects CS can exert on pulmonary epithelia at the protein level. We, therefore, tested the hypothesis that CS exerts direct effects on the CFTR protein, which could impair airway hydration, leading to the mucus stasis characteristic of both cystic fibrosis and CB. In vivo and in vitro studies demonstrated that CS rapidly decreased CFTR activity, leading to airway surface liquid (ASL) volume depletion (i.e., dehydration). Further studies revealed that CS induced internalization of CFTR. Surprisingly, CS-internalized CFTR did not colocalize with lysosomal proteins. Instead, the bulk of CFTR shifted to a detergent-resistant fraction within the cell and colocalized with the intermediate filament vimentin, suggesting that CS induced CFTR movement into an aggresome-like, perinuclear compartment. To test whether airway dehydration could be reversed, we used hypertonic saline (HS) as an osmolyte to rehydrate ASL. HS restored ASL height in CS-exposed, dehydrated airway cultures. Similarly, inhaled HS restored mucus transport and increased clearance in patients with CB. Thus, we propose that CS exposure rapidly impairs CFTR function by internalizing CFTR, leading to ASL dehydration, which promotes mucus stasis and a failure of mucus clearance, leaving smokers at risk for developing CB. Furthermore, our data suggest that strategies to rehydrate airway surfaces may provide a novel form of therapy for patients with CB.-Clunes, L. A., Davies, C. M., Coakley, R. D., Aleksandrov, A. A., Henderson, A. G., Zeman, K. L., Worthington, E. N., Gentzsch, M., Kreda, S. M., Cholon, D., Bennett, W. D., Riordan, J. R., Boucher, R. C., Tarran, R. Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration. FASEB J. 26, 533-545 (2012). www.fasebj.org