title: Interdependency of beta-adrenergic receptors and CFTR in regulation of alveolar active Na+ transport.
abstract: Beta-adrenergic receptors (betaAR) regulate active Na+ transport in the alveolar epithelium and accelerate clearance of excess airspace fluid. Accumulating data indicates that the cystic fibrosis transmembrane conductance regulator (CFTR) is important for upregulation of the active ion transport that is needed to maintain alveolar fluid homeostasis during pulmonary edema. We hypothesized that betaAR regulation of alveolar active transport may be mediated via a CFTR dependent pathway. To test this hypothesis we used a recombinant adenovirus that expresses a human CFTR cDNA (adCFTR) to increase CFTR function in the alveolar epithelium of normal rats and mice. Alveolar fluid clearance (AFC), an index of alveolar active Na+ transport, was 92% greater in CFTR overexpressing lungs than controls. Addition of the Cl- channel blockers NPPB, glibenclamide, or bumetanide and experiments using Cl- free alveolar instillate solutions indicate that the accelerated AFC in this model is due to increased Cl- channel function. Conversely, CFTR overexpression in mice with no beta1- or beta2-adrenergic receptors had no effect on AFC. Overexpression of a human beta2AR in the alveolar epithelium significantly increased AFC in normal mice but had no effect in mice with a non-functional human CFTR gene (Deltaphi508 mutation). These studies indicate that upregulation of alveolar CFTR function speeds clearance of excess fluid from the airspace and that CFTRs effect on active Na+ transport requires the betaAR. These studies reveal a previously undetected interdependency between CFTR and betaAR that is essential for upregulation of active Na+ transport and fluid clearance in the alveolus.
authors.affiliation: Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill, USA.
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
authors.forename: Yochai
authors.initials: Y
authors.lastname: Adir
authors.forename: Mohammed
authors.initials: M
authors.lastname: Jameel
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Akhmedov
authors.forename: Lynn
authors.initials: L
authors.lastname: Welch
authors.forename: Vidas
authors.initials: V
authors.lastname: Dumasius
authors.forename: Fan Jing
authors.initials: FJ
authors.lastname: Meng
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
authors.forename: Craig
authors.initials: C
authors.lastname: Koenig
authors.forename: Erin Rachel
authors.initials: ER
authors.lastname: Lewis
authors.forename: Rajesh
authors.initials: R
authors.lastname: Balagani
authors.forename: Geri
authors.initials: G
authors.lastname: Traver
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
authors.forename: Phillip
authors.initials: P
authors.lastname: Factor
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D018014:Gene Transfer Techniques; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000378:metabolism*; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D015222:Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase