Interdependency of -Adrenergic Receptors and CFTR in Regulation of Alveolar Active Na Transport

-Adrenergic receptors ( AR) 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 AR 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 1or 2-adrenergic receptors had no effect on AFC. Overexpression of a human 2AR in the alveolar epithelium significantly increased AFC in normal mice but had no effect in mice with a non-functional human CFTR gene ( 508 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 AR. These studies reveal a previously undetected interdependency between CFTR and AR that is essential for upregulation of active Na transport and fluid clearance in the alveolus. (Circ Res. 2005;96:999-1005.)