Abstract
Alcohol abuse is associated with increased lung infections. Molecular understanding of the underlying mechanisms is not complete. Airway epithelial ion transport regulates the homeostasis of airway surface liquid, essential for airway mucosal immunity and lung host defense. Here, air-liquid interface cultures of Calu-3 epithelial cells were basolaterally exposed to physiologically relevant concentrations of ethanol (0, 25, 50 and 100 mM) for 24 hours and adenosine-stimulated ion transport was measured by Ussing chamber. The ethanol exposure reduced the epithelial short-circuit currents (ISC) in a dose-dependent manner. The ion currents activated by adenosine were chloride conductance mediated by cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel. Alloxazine, a specific inhibitor for A2B adenosine receptor (A2BAR), largely abolished the adenosine-stimulated chloride transport, suggesting that A2BAR is a major receptor responsible for regulating the chloride transport of the cells. Ethanol significantly reduced intracellular cAMP production upon adenosine stimulation. Moreover, ethanol-suppression of the chloride secretion was able to be restored by cAMP analogs or by inhibitors to block cAMP degradation. These results imply that ethanol exposure dysregulates CFTR-mediated chloride transport in airways by suppression of adenosine-A2BAR-cAMP signaling pathway, which might contribute to alcohol-associated lung infections.
Highlights
Alcohol abuse is a risk factor for pulmonary infections
The cultured epithelia were exposed basolaterally for 24 hours to different concentrations of ethanol (0, 25, 50 and 100 mM) and adenosineinduced transepithelial ion transport was assessed by measuring ISC with an Ussing chamber apparatus
Airway epithelial cells constitute the physical barrier that separates airway lumen from interstitial compartments, and actively participate in innate and adaptive immunity to protect the host from pulmonary infections [33]
Summary
Alcohol abuse is a risk factor for pulmonary infections. It is not fully understood how alcohol exposure compromises the lung host defense. Airway mucosal immunity and mucociliary clearance are the two primary host defense mechanisms, which take place in a thin layer of liquid on the top of airway epithelia, known as airway surface liquid (ASL). ASL, composed of a gel-like mucus layer and a sol-like periciliary liquid layer [4,5,6], is the ‘‘battlefield’’ for pulmonary infection and immunity. PCL prevents cilia from being entrapped in viscous mucus and bathes them for mechanical movement for mucociliary clearance [5,10]
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