Upregulation of Alveolar Epithelial Active Na + Transport Is Dependent on β 2 -Adrenergic Receptor Signaling

Alveolar epithelial β-adrenergic receptor (βAR) 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 β 1 - or β 2 -adrenergic receptors (β 1 AR −/− /β 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 βAR signaling may not be required for alveolar fluid homeostasis in uninjured lungs. Comparison of isoproterenol-sensitive AFC in mice with β 1 - but not β 2 -adrenergic receptors to β 1 AR −/− /β 2 AR −/− mice indicates that the β 2 AR mediates the bulk of β-adrenergic-sensitive alveolar active Na + transport. To test the necessity of βAR signaling in acute lung injury, β 1 AR −/− /β 2 AR −/− , β 1 AR +/+ /β 2 AR −/− , and β 1 AR +/+ /β 2 AR +/+ mice were exposed to 100% oxygen for up to 204 hours. β 1 AR −/− /β 2 AR −/− and β 1 AR +/+ /β 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 β 2 -adrenergic receptor (β 2 AR) function into the alveolar epithelium of β 1 AR −/− /β 2 AR −/− and β 1 AR +/+ /β 2 AR −/− mice normalized distal lung β 2 AR function, alveolar epithelial active Na + transport, and survival from hyperoxia. These findings indicate that βAR signaling may not be necessary for basal AFC, and that β 2 AR is essential for the adaptive physiological response needed to clear excess fluid from the alveolar airspace of normal and injured lungs.