beta(2)-adrenergic receptor overexpression increases alveolar fluid clearance and responsiveness to endogenous catecholamines in rats

beta -Adrenergic agonists accelerate the clearance of alveolar fluid by inc reasing the expression and activity of epithelial solute transport proteins such as amiloride-sensitive epithelial Na+ channels (ENaC) and Na,K-ATPase s. Here we report that adenoviral-mediated overexpression of a human beta ( 2)-adrenergic receptor (beta (2)AR) cDNA increases beta (2)AR mRNA, membran e-bound receptor protein expression, and receptor function (procaterol-indu ced cAMP production) in human lung epithelial cells (A549). Receptor overex pression was associated with increased catecholamine (procaterol)responsive active Na+ transport and increased abundance of Na,K-ATPases in the basola teral cell membrane. beta (2)AR gene transfer to the alveolar epithelium of normal rats improved membrane-bound beta (2)AR expression and function and increased levels of ENaC (alpha subunit) abundance and Na,K-ATPases activi ty in apical and basolateral cell membrane fractions isolated from the peri pheral lung, respectively. Alveolar fluid clearance (AFC), an index of acti ve Na+ transport, in beta (2)AR overexpressing rats was up to 100% greater than sham-infected controls and rats infected with an adenovirus that expre sses no cDNA. The addition of the beta (2)AR-specific agonist procaterol to beta (2)AR overexpressing lungs did not increase AFC further. AFC in beta (2)AR overexpressing lungs from adrenalectomized or propranolol-treated rat s revealed clearance rates that were the same or less than normal, untreate d, sham-infected controls. These experiments indicate that alveolar beta (2 )AR overexpression improves beta (2)AR function and maximally upregulates b eta -agonist-responsive active Na+ transport by improving responsiveness to endogenous catecholamines. These studies suggest that upregulation o beta (2)AR function may someday prove useful for the treatment of pulmonary edem a.