Published online before print March 11, 2004, doi: 10.1161/01.RES.0000125623.56442.20
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Submitted on September 29, 2003
Revised on February 26, 2004
Accepted on March 2, 2004
Upregulation of Alveolar Epithelial Active Na+ Transport Is Dependent on 
2-Adrenergic Receptor Signaling
Gökhan M. Mutlu ;
From the Division of Pulmonary and Critical Care Medicine (G.M.M., L.W.), Northwestern University Feinberg School of Medicine, Chicago, Ill; University of Illinois College of Medicine (G.M.M.), Chicago, Ill; Evanston Northwestern Healthcare Research Institute (J.B., F.J.M., N.M.), Evanston, Ill; Division of Pulmonary and Critical Care Medicine (P.J.M.), University of Rochester, Rochester, NY; Rush Presbyterian St Lukes Hospital (A.D.), Chicago, Ill; Department of Anesthesiology (K.H., S.M.), University of Alabama at Birmingham, Birmingham, Ala; Section of Cardiology (S.H.), Cooper Hospital/University Medical Center, Camden, NJ; Division of Pulmonary (P.F.), Allergy and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, NY.
* To whom correspondence should be addressed. E-mail: phf2103{at}columbia.edu.
Alveolar epithelial 
-adrenergic receptor (AR) 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 1- or 2-adrenergic receptors (1AR-/-/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 AR signaling may not be required for alveolar fluid homeostasis in uninjured lungs. Comparison of isoproterenol-sensitive AFC in mice with 1- but not 2-adrenergic receptors to 1AR-/-/2AR-/- mice indicates that the 2AR mediates the bulk of -adrenergic-sensitive alveolar active Na+ transport. To test the necessity of AR signaling in acute lung injury, 1AR-/-/2AR-/-, 1AR+/+/2AR-/-, and 1AR+/+/2AR+/+ mice were exposed to 100% oxygen for up to 204 hours. 1AR-/-/2AR-/- and 1AR+/+/2AR-/- mice had more lung water and worse survival from this form of acute lung injury than wild-type controls. Adenoviral-mediated rescue of 2-adrenergic receptor (2AR) function into the alveolar epithelium of 1AR-/-/2AR-/- and 1AR+/+/2AR-/- mice normalized distal lung 2AR function, alveolar epithelial active Na+ transport, and survival from hyperoxia. These findings indicate that AR signaling may not be necessary for basal AFC, and that 2AR is essential for the adaptive physiological response needed to clear excess fluid from the alveolar airspace of normal and injured lungs.
Key words: alveolar fluid clearance • pulmonary edema •
2-adrenergic receptor •
adenovirus •
Na+ channel
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