title: Suppression of adenosine-activated chloride transport by ethanol in airway epithelia.
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 (I(SC)) 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 A(2B) adenosine receptor (A(2B)AR), largely abolished the adenosine-stimulated chloride transport, suggesting that A(2B)AR 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-A(2B)AR-cAMP signaling pathway, which might contribute to alcohol-associated lung infections.
authors.affiliation: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Sammeta V
authors.initials: SV
authors.lastname: Raju
authors.forename: Guoshun
authors.initials: G
authors.lastname: Wang
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D000437:Alcoholism / Q000150:complications / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology*; D002460:Cell Line; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D005415:Flavins / Q000494:pharmacology; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D008171:Lung Diseases / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
chemical_list: D000700:Analgesics; C505032:CFTR protein, human; D002492:Central Nervous System Depressants; D002712:Chlorides; D005415:Flavins; D043704:Receptor, Adenosine A2B; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000431:Ethanol; C008173:isoalloxazine; D000242:Cyclic AMP; D000241:Adenosine