Upregulation of alveolar epithelial active Na+ transport is dependent on β2-adrenergic receptor signaling

Alveolar epithelial beta-adrenergic receptor (betaAR) activation accelerates active Na+ transport in lung epithelial cells in vitro and speeds alveolar edema resolution in human lung tissue and normal and injured animal lungs. Whether these receptors are essential for alveolar fluid clearance (AFC) or if other mechanisms are sufficient to regulate active transport is unknown. In this study, we report that mice with no beta(1)- or beta(2)-adrenergic receptors (beta(1)AR(-/-)/beta(2)AR(-/-)) have reduced distal lung Na, K-ATPase function and diminished basal and amiloride-sensitive AFC. Total lung water content in these animals was not different from wild-type controls, suggesting that betaAR signaling may not be required for alveolar fluid homeostasis in uninjured lungs. Comparison of isoproterenol-sensitive AFC in mice with beta(1)- but not beta(2)-adrenergic receptors to beta(1)AR(-/-)/beta(2)AR(-/-) mice indicates that the beta(2)AR mediates the bulk of beta-adrenergic-sensitive alveolar active Na+ transport. To test the necessity of betaAR signaling in acute lung injury, beta(1)AR(-/-)/beta(2)AR(-/-), beta(1)AR(+/+)/beta(2)AR(-/-), and beta(1)AR(+/+)/beta(2)AR(+/+) mice were exposed to 100% oxygen for up to 204 hours. beta(1)AR(-/-)/beta(2)AR(-/-) and beta(1)AR(+/+)/beta(2)AR(-/-) mice had more lung water and worse survival from this form of acute lung injury than wild-type controls. Adenoviral-mediated rescue of beta(2)-adrenergic receptor (beta(2)AR) function into the alveolar epithelium of beta(1)AR(-/-)/beta(2)AR(-/-) and beta(1)AR(+/+)/beta(2)AR(-/-) mice normalized distal lung beta(2)AR function, alveolar epithelial active Na+ transport, and survival from hyperoxia. These findings indicate that betaAR signaling may not be necessary for basal AFC, and that beta(2)AR is essential for the adaptive physiological response needed to clear excess fluid from the alveolar airspace of normal and injured lungs.