酒精诱导的黏液纤毛功能障碍：囊性纤维化跨膜传导调节因子（CFTR）通道功能缺陷的作用。
Alcohol-Induced Mucociliary Dysfunction: Role of Defective CFTR Channel Function.
作者信息
Rasmussen Lawrence, Stafford Denise, LaFontaine Jennifer, Allen Antonio, Antony Linto, Kim Hyunki, Raju S Vamsee
机构信息
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Environment Health Science, University of Alabama at Birmingham, Birmingham, AL, USA.
出版信息
bioRxiv. 2023 Jul 19:2023.07.17.548927. doi: 10.1101/2023.07.17.548927.
UNLABELLED
Excessive alcohol use is thought to increase the risk of respiratory infections by impairing mucociliary clearance (MCC). In this study, we investigate the hypothesis that alcohol reduces the function of CFTR, the protein that is defective in individuals with cystic fibrosis, thus altering mucus properties to impair MCC and the airway's defense against inhaled pathogens.
METHODS
Sprague Dawley rats with wild type CFTR (+/+), matched for age and sex, were administered either a Lieber-DeCarli alcohol diet or a control diet with the same number of calories for eight weeks. CFTR activity was measured using nasal potential difference (NPD) assay and Ussing chamber electrophysiology of tracheal tissue samples. In vivo MCC was determined by measuring the radiographic clearance of inhaled Tc99 particles and the depth of the airway periciliary liquid (PCL) and mucus transport rate in excised trachea using micro-optical coherence tomography (μOCT). The levels of rat lung MUC5b and CFTR were estimated by protein and mRNA analysis.
RESULTS
Alcohol diet was found to decrease CFTR ion transport in the nasal and tracheal epithelium and . This decrease in activity was also reflected in partially reduced full-length CFTR protein levels but not, in mRNA copies, in the lungs of rats. Furthermore, alcohol-fed rats showed a significant decrease in MCC after 8 weeks of alcohol consumption. The trachea from these rats also showed reduced PCL depth, indicating a decrease in mucosal surface hydration that was reflected in delayed mucus transport. Diminished MCC rate was also likely due to the elevated MUC5b expression in alcohol-fed rat lungs.
CONCLUSIONS
Excessive alcohol use can decrease the expression and activity of CFTR channels, leading to reduced airway surface hydration and impaired mucus clearance. This suggests that CFTR dysfunction plays a role in the compromised lung defense against respiratory pathogens in individuals who drink alcohol excessively.
未标注
过量饮酒被认为会通过损害黏液纤毛清除功能（MCC）增加呼吸道感染风险。在本研究中，我们调查了以下假说：酒精会降低囊性纤维化患者体内有缺陷的蛋白质CFTR的功能，从而改变黏液特性，损害MCC以及气道对吸入病原体的防御能力。
方法
将年龄和性别匹配的野生型CFTR（+/+）的Sprague Dawley大鼠给予Lieber-DeCarli酒精饮食或相同热量的对照饮食，持续八周。使用鼻电位差（NPD）测定法和气管组织样本的尤斯灌流小室电生理学来测量CFTR活性。通过测量吸入的Tc99颗粒的放射性清除率以及使用微光学相干断层扫描（μOCT）测量离体气管中的气道周缘液体（PCL）深度和黏液运输速率来确定体内MCC。通过蛋白质和mRNA分析估计大鼠肺中MUC5b和CFTR的水平。
结果
发现酒精饮食会降低鼻腔和气管上皮中的CFTR离子转运。这种活性降低也反映在大鼠肺中全长CFTR蛋白水平部分降低，但mRNA拷贝数未降低。此外，饮酒8周后，酒精喂养的大鼠的MCC显著降低。这些大鼠的气管还显示PCL深度降低，表明黏膜表面水合作用降低，这反映在黏液运输延迟上。MCC速率降低也可能是由于酒精喂养的大鼠肺中MUC5b表达升高。
结论
过量饮酒会降低CFTR通道的表达和活性，导致气道表面水合作用降低和黏液清除受损。这表明CFTR功能障碍在过度饮酒个体的肺部对呼吸道病原体防御受损中起作用。
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