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A7631 - Role of Acquired CFTR Dysfunction in Alcohol Impairment of Mucus Clearance
Author Block: L. W. Rasmussen1, D. Stanford2, J. LaFontaine1, S. E. Phillips1, K. Hyunki1, K. Patel1, L. Tang1, C. M. Evans3, S. M. Rowe2, T. Schoeb1, S. Bailey1, W. E. Swords4, E. L. Burnham5, S. Raju2; 1University of Alabama Birmingham, Birmingham, AL, United States, 2University of Alabama at Birmingham, Birmingham, AL, United States, 3Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver School of Medicine, Aurora, CO, United States, 4Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States, 5Univ of Colorado Denver, Denver, CO, United States.
INTRODUCTION: Impairment of mucociliary clearance (MCC) is considered to increase risk of respiratory infections among excessive alcohol users. The mechanisms underlying this impact of alcohol on MCC are not currently understood. Our previous in vitro studies indicated that alcohol decreases ion transport via CFTR channels, the defective protein that causes cystic fibrosis. Here, we have attempted to validate these findings in vivo and test the hypothesis that alcohol-induced CFTR dysfunction reduces airway surface hydration and mucus transport thereby impairing airway defense against inhaled bacterial pathogens, in particular Klebsiella pneumoniae, to which alcohol users are susceptible.
METHODS: Age and gender-matched rats (CFTR+/+) were pair-fed with Lieber-DeCarli alcohol diet or isocaloric control diet for 4 weeks and with K. pneumoniae (KP, ATCC 43816). CFTR activity was measured with nasal potential difference (NPD) and MCC was assayed with radiographic clearance of Tc99. Airway surface liquid (ASL), periciliary layer (PCL), and ciliary beat frequency (CBF) of excised trachea were quantified with micro-optical coherence tomography (µOCT). Expression of CFTR and MUC5B were assessed in bronchoalveolar lavage (BAL) and bronchial brushings from healthy participants and those with a history of alcohol use disorders (AUDs) per Alcohol Use Disorders Identification Test (AUDIT).
RESULTS: Alcohol administration reduced CFTR ion transport by NPD (ΔCl- free + forskolin in mV, -13.7 ± 1.0 Alcohol vs. -21.0 ± 2.4 Control, P≤0.01). Clearance of Tc99 label in 30 min indicated delayed MCC in alcohol-treated rats (22.7 %± 4.4 Alcohol vs. 39.1 ± 4.8% Control, P≤0.01). Trachea excised from alcohol-treated rats exhibited decreased PCL depth (3.3 ± 0.05 Alcohol vs. 4.7 ± 0.5 µm Control, P≤0.01), but no meaningful differences in ASL or CBF. Analysis of lung tissues indicated reduced expression of CFTR mRNA and protein and increased AB-PAS mucus staining and Muc5b protein expression. Compared to controls, histopathological examination of lung sections from alcohol-treated animals exhibited more severe evidence of multifocal pneumonia with edema, fibrin deposition and numerous bacteria in alveolar spaces. Expression studies were supported by decreased CFTR mRNA expression in bronchial biopsies and elevated MUC5B protein in BAL from AUD subjects.
CONCLUSIONS: Alcohol-induced defects in CFTR ion transport resulted in reduced airway surface hydration and delayed mucus clearance in rat airways that was associated with mucus hypersecretion and diminished ability to clear bacterial pathogens. These data implicate a role for CFTR as a proximate cause of compromised lung mucosal defense leading to an increased incidence of pneumonia among alcohol abusers.