title: Adenosine regulation of alveolar fluid clearance.
abstract: Adenosine is a purine nucleoside that regulates cell function through G protein-coupled receptors that activate or inhibit adenylyl cyclase. Based on the understanding that cAMP regulates alveolar epithelial active Na(+) transport, we hypothesized that adenosine and its receptors have the potential to regulate alveolar ion transport and airspace fluid content. Herein, we report that type 1 (A(1)R), 2a (A(2a)R), 2b (A(2b)R), and 3 (A(3)R) adenosine receptors are present in rat and mouse lungs and alveolar type 1 and 2 epithelial cells (AT1 and AT2). Rat AT2 cells generated and produced cAMP in response to adenosine, and micromolar concentrations of adenosine were measured in bronchoalveolar lavage fluid from mice. Ussing chamber studies of rat AT2 cells indicated that adenosine affects ion transport through engagement of A(1)R, A(2a)R, and/or A(3)R through a mechanism that increases CFTR and amiloride-sensitive channel function. Intratracheal instillation of low concentrations of adenosine (< or =10(-8)M) or either A(2a)R- or A(3)R-specific agonists increased alveolar fluid clearance (AFC), whereas physiologic concentrations of adenosine (> or =10(-6)M) reduced AFC in mice and rats via an A(1)R-dependent pathway. Instillation of a CFTR inhibitor (CFTR(inh-172)) attenuated adenosine-mediated down-regulation of AFC, suggesting that adenosine causes Cl(-) efflux by means of CFTR. These studies report a role for adenosine in regulation of alveolar ion transport and fluid clearance. These findings suggest that physiologic concentrations of adenosine allow the alveolar epithelium to counterbalance active Na(+) absorption with Cl(-) efflux through engagement of the A(1)R and raise the possibility that adenosine receptor ligands can be used to treat pulmonary edema.
authors.affiliation: Pulmonary, Allergy, and Critical Care Medicine, Columbia University, 639 West 168th Street, New York, NY 10027, USA. phf2103@columbia.edu
authors.forename: Phillip
authors.initials: P
authors.lastname: Factor
authors.forename: Göskhan M
authors.initials: GM
authors.lastname: Mutlu
authors.forename: Lan
authors.initials: L
authors.lastname: Chen
authors.forename: Jameel
authors.initials: J
authors.lastname: Mohameed
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Akhmedov
authors.forename: Fan Jing
authors.initials: FJ
authors.lastname: Meng
authors.forename: Tamas
authors.initials: T
authors.lastname: Jilling
authors.forename: Erin Rachel
authors.initials: ER
authors.lastname: Lewis
authors.forename: Meshell D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Anna
authors.initials: A
authors.lastname: Xu
authors.forename: Daniel
authors.initials: D
authors.lastname: Kass
authors.forename: Janice M
authors.initials: JM
authors.lastname: Martino
authors.forename: Amy
authors.initials: A
authors.lastname: Bellmeyer
authors.forename: John S
authors.initials: JS
authors.lastname: Albazi
authors.forename: Charles
authors.initials: C
authors.lastname: Emala
authors.forename: H T
authors.initials: HT
authors.lastname: Lee
authors.forename: Leland G
authors.initials: LG
authors.lastname: Dobbs
authors.forename: Sadis
authors.initials: S
authors.lastname: Matalon
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001992:Bronchoalveolar Lavage Fluid; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D015536:Down-Regulation; D004594:Electrophysiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000378:metabolism*; D051381:Rats; D012964:Sodium / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012964:Sodium; D000242:Cyclic AMP; D000241:Adenosine