Upregulation of Alveolar Epithelial Active Na+ Transport Is Dependent on β2-Adrenergic Receptor Signaling

GM Mutlu, V Dumasius, J Burhop, PJ McShane… - Circulation …, 2004 - Am Heart Assoc
GM Mutlu, V Dumasius, J Burhop, PJ McShane, FJ Meng, L Welch, A Dumasius…
Circulation research, 2004Am Heart Assoc
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 β1-or β2-adrenergic receptors
(β1AR−/−/β2AR−/−) have reduced distal lung Na, K-ATPase function and diminished basal …
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 β1- or β2-adrenergic receptors (β1AR−/−2AR−/−) 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 β1- but not β2-adrenergic receptors to β1AR−/−2AR−/− mice indicates that the β2AR mediates the bulk of β-adrenergic-sensitive alveolar active Na+ transport. To test the necessity of βAR signaling in acute lung injury, β1AR−/−2AR−/−, β1AR+/+2AR−/−, and β1AR+/+2AR+/+ mice were exposed to 100% oxygen for up to 204 hours. β1AR−/−2AR−/− and β1AR+/+2AR−/− mice had more lung water and worse survival from this form of acute lung injury than wild-type controls. Adenoviral-mediated rescue of β2-adrenergic receptor (β2AR) function into the alveolar epithelium of β1AR−/−2AR−/− and β1AR+/+2AR−/− mice normalized distal lung β2AR 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 β2AR is essential for the adaptive physiological response needed to clear excess fluid from the alveolar airspace of normal and injured lungs.
Am Heart Assoc