PDE4 Inhibitor Reverses Alcohol Impairment of CFTR Function and Protects Against Bacterial Pneumonia

Abstract

INTRODUCTIONAlcohol is a significant risk factor for respiratory infections. Excessive alcohol users suffer from more frequent lung infections, severe symptoms, and poor antibiotic response. Mucociliary clearance (MCC) is a primary lung defense mechanism against inhaled/aspirated pathogens and is impaired by alcohol use. Previously, we found diminished MCC associates with reduced CFTR‐mediated ion transport in alcohol‐fed rats. In addition, CFTR dysfunction correlated with increased cAMP degradation by phosphodiesterase‐4 (PDE4) enzymes and reduced channel gating. Here, we test whether roflumilast, a clinically used PDE4 inhibitor, can preserve cAMP levels in alcohol‐fed rats and promote CFTR function and clearance of Klebsiella pneumoniae (KP, ATCC 43816), to which alcohol users are disproportionately susceptible.METHODSAge and gender‐matched rats (CFTR+/+) were pair‐fed with Lieber‐DeCarli alcohol diet or isocaloric control diet for eight weeks. CFTR activity was assayed by Ussing chamber electrophysiology of tracheal explants. Rats were randomly treated with vehicle/roflumilast (5mg/kg/day) by oral gavage starting 7 days before the end of 8‐week alcohol diet. Airway surface liquid (ASL) depth, periciliary layer (PCL) height, mucus viscosity, and transport (MCT) on excised trachea were quantified with micro‐optical coherence tomography (µOCT) imaging. In addition, lung function was assessed by flexivent oscillometry.RESULTSAlcohol administration reduced CFTR‐mediated ion transport in rat airways. µOCT image analysis of excised trachea from these rats indicated decreased PCL depth and increased mucus viscosity. Despite the normal ciliary beating, there was a noticeable delay in MCT in alcohol‐fed rats. Roflumilast treatment significantly increased CFTR activity in both control and alcohol‐administered rats. Increased CFTR activation by roflumilast resulted in augmented PCL depth, reduced mucus viscosity, and significantly accelerated MCT rate. While roflumilast partially improved clearance of KP, there was pronounced protection against increased airway resistance and lung injury. Histopathological examination of lung sections indicates roflumilast reduced the severity of multifocal pneumonia with edema, fibrin deposition, and numerous bacteria in alveolar spaces. These improvements were more evident in control rats over those administered with alcohol. Ongoing studies are exploring how roflumilast altered immune cell recruitment and inflammatory signaling to reduce infectious injury.CONCLUSIONSAcquired (non‐genetic) CFTR dysfunction may be a suitable target to improve mucus clearance impaired by alcohol use. Administration of PDE4 inhibitors such as roflumilast may boost lung host defense against bacterial pathogens and improve pneumonia outcomes in individuals affected by excessive alcohol use.