title: A2B adenosine receptors regulate the mucus clearance component of the lung's innate defense system.
abstract: Adenosine (ADO) signaling is altered in both asthma and chronic obstructive pulmonary disease, and the A(2B) adenosine receptor (A(2B)-R) may drive pulmonary inflammation. Accordingly, it has been proposed that specific inhibition of the A(2B)-R could treat inflammatory lung diseases. However, stimulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by ADO may be crucial in permitting the superficial epithelium to maintain airway surface liquid (ASL) volume, which is required to ensure hydrated and clearable mucus. Our goal was to determine which ADO receptor (ADO-R) underlies ASL volume regulation in bronchial epithelia. We used PCR techniques to determine ADO-R expression in bronchial epithelia and used nasal potential difference measurements, Ussing chambers studies, and XZ-confocal microscopy to look at Cl- secretion and ASL volume regulation. The A(2B)-R was the most highly expressed ADO-R in donor specimens of human bronchial epithelia, and inhibition of ADO-R in vivo prevented activation of CFTR. A(2B)-R was the only ADO-R detected in cultured human bronchial epithelial cells and inhibition of this receptor with specific A(2B)-R antagonists resulted in ASL height collapse and a failure to effect ASL height homeostasis. Removal of ADO with ADO deaminase and replacement with 5'N-ethylcarboxamide adenosine resulted in dose-dependent changes in ASL height, and suggested that the cell surface (ADO) may be in excess of 1 microM, which is sufficient to activate A(2B)-R. A(2B)-R are required for ASL volume homeostasis in human airways, and therapies directed at inhibiting A(2B)-R may lead to a cystic fibrosis-like phenotype with depleted ASL volume and mucus stasis.
authors: Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina, Chapel Hill, North Carolina, USA.
authors: Brett M
authors: BM
authors: Rollins
authors: Mellisa
authors: M
authors: Burn
authors: Ray D
authors: RD
authors: Coakley
authors: Lucy A
authors: LA
authors: Chambers
authors: Andrew J
authors: AJ
authors: Hirsh
authors: Mark T
authors: MT
authors: Clunes
authors: Michael I
authors: MI
authors: Lethem
authors: Scott H
authors: SH
authors: Donaldson
authors: Robert
authors: R
authors: Tarran
mesh_terms: D000241:Adenosine / Q000494:pharmacology / Q000502:physiology*; D058917:Adenosine A2 Receptor Antagonists; D000243:Adenosine Deaminase / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D001980:Bronchi / Q000276:immunology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D009093:Mucus / Q000502:physiology*; D043704:Receptor, Adenosine A2B / Q000096:biosynthesis / Q000502:physiology*; D020545:Respiratory Mucosa / Q000276:immunology / Q000502:physiology*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D002712:Chlorides; D043704:Receptor, Adenosine A2B; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019830:Adenosine-5'-(N-ethylcarboxamide); D000242:Cyclic AMP; D000243:Adenosine Deaminase; D000241:Adenosine; D002118:Calcium