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(Circulation Research. 2004;94:1091.)
© 2004 American Heart Association, Inc.

Cellular Biology

Upregulation of Alveolar Epithelial Active Na⁺ Transport Is Dependent on ß₂-Adrenergic Receptor Signaling

Gökhan M. Mutlu, Vidas Dumasius, James Burhop, Pamela J. McShane, Fan Jing Meng, Lynn Welch, Andrew Dumasius, Nima Mohebahmadi, Gloria Thakuria, Karen Hardiman, Sadis Matalon, Steven Hollenberg, Phillip Factor

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 (V.D.), 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.

Correspondence to Phillip Factor, DO, Pulmonary, Allergy and Critical Care Medicine, Columbia University College of Physicians and Surgeons, P&S 10-502, 630 W 168th St, New York, NY 10032. E-mail phf2103{at}columbia.edu

Alveolar epithelial ß-adrenergic receptor (ßAR) 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 ß₁- or ß₂-adrenergic receptors (ß₁AR^–/–/ß₂AR^–/–) 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 ßAR signaling may not be required for alveolar fluid homeostasis in uninjured lungs. Comparison of isoproterenol-sensitive AFC in mice with ß₁- but not ß₂-adrenergic receptors to ß₁AR^–/–/ß₂AR^–/– mice indicates that the ß₂AR mediates the bulk of ß-adrenergic-sensitive alveolar active Na⁺ transport. To test the necessity of ßAR signaling in acute lung injury, ß₁AR^–/–/ß₂AR^–/–, ß₁AR^+/+/ß₂AR^–/–, and ß₁AR^+/+/ß₂AR^+/+ mice were exposed to 100% oxygen for up to 204 hours. ß₁AR^–/–/ß₂AR^–/– and ß₁AR^+/+/ß₂AR^–/– mice had more lung water and worse survival from this form of acute lung injury than wild-type controls. Adenoviral-mediated rescue of ß₂-adrenergic receptor (ß₂AR) function into the alveolar epithelium of ß₁AR^–/–/ß₂AR^–/– and ß₁AR^+/+/ß₂AR^–/– mice normalized distal lung ß₂AR function, alveolar epithelial active Na⁺ transport, and survival from hyperoxia. These findings indicate that ßAR signaling may not be necessary for basal AFC, and that ß₂AR 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 • ß₂-adrenergic receptor • adenovirus • Na⁺ channel

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