Alcohol-Induced Mucociliary Dysfunction: Role of Defective CFTR Channel Function

Abstract

ABSTRACTExcessive 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.MethodsSprague 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.ResultsAlcohol diet was found to decrease CFTR ion transport in the nasal and tracheal epitheliumin vivoandex vivo. 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.ConclusionsExcessive 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.What is the current scientific knowledge on this subject?Excessive alcohol is associated with delayed mucociliary clearance (MCC) and an increased risk of respiratory infections among heavy drinkers.What does this study add to the field?Chronic alcohol use reduces CFTR activity and airway surface hydration explaining the mechanisms underlying mucociliary dysfunction. Acquired CFTR dysfunction may be a suitable target to improve host immunity in those affected by prolonged alcohol use.