Abstract-Alveolar epithelial ␤-adrenergic receptor (␤AR) activation accelerates active Na ϩ 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 (␤ 1 AR Ϫ/Ϫ /␤ 2 AR Ϫ/Ϫ ) 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 ␤ 1 AR Ϫ/Ϫ /␤ 2 AR Ϫ/Ϫ mice indicates that the ␤ 2 AR mediates the bulk of ␤-adrenergic-sensitive alveolar active Na ϩ transport. To test the necessity of ␤AR signaling in acute lung injury, Key Words: alveolar fluid clearance Ⅲ pulmonary edema Ⅲ ␤ 2 -adrenergic receptor Ⅲ adenovirus Ⅲ Na ϩ channel T he combined action of alveolar epithelial Na ϩ channels (ENaCs), the cystic fibrosis transmembrane conductance regulator (CFTR), Na,K-ATPases, and K ϩ channels creates the transepithelial Na ϩ gradient needed for the transit of excess fluid from the alveolar airspace. 1,2 The importance of these proteins to this energy-dependent (ie, active) process is evidenced by data showing that their inhibition reduces the lung's ability to clear excess alveolar fluid [3][4][5][6][7] and that their upregulation confers protection from acute injury. 4,8,9 Despite these extensive investigations, the mechanisms by which these proteins are upregulated in response to excess alveolar fluid (pulmonary edema) are not well resolved.One possible pathway for upregulation of alveolar-active Na ϩ transport is ␤-adrenergic receptor activation. Stimulation of alveolar epithelial ␤ARs by endogenous or exogenous catecholamines accelerates active Na ϩ transport in lung epithelial cells in vitro and in experimental in vivo systems by increasing the expression and/or function of epithelial transport proteins. 10 -12 Thus, this G protein-dependent pathway represents a mechanism by which the lung can alter its physiology to adapt to and protect itself from excess alveolar fluid. What is not known is if ␤AR signaling is essential for the regulation of alveolar active Na ϩ transport or whether other mechanisms (eg, intracellular osmo-, redox-, or chemosensitive regulators) can enhance alveolar active transport to clear pulmonary edema.The present study was structured to define what contribution alveolar epithelial ␤ARs make to active Na ϩ transport in the alveolar epithelium of normal mice and mice with acute lung injury caused by exposure to hyperoxia. Herein, we show that distal lung transport protein function and the lung's ability to clear excess alveolar fluid is highly dependent on Materials an...

Familial hypertrophic cardiomyopathy (FHC) is caused by missense or premature truncation mutations in proteins of the cardiac contractile apparatus. Mutant proteins are incorporated into the thin filament or thick filament and eventually produce cardiomyopathy. However, it has been unclear how the several, genetically identified defects in protein structure translate into impaired protein and muscle function. We have studied the basis of FHC caused by premature truncation of the most frequently implicated thin filament target, troponin T. Electron microscope observations showed that the thin filament undergoes normal structural changes in response to Ca 2؉ binding. On the other hand, solution studies showed that the mutation alters and destabilizes troponin binding to the thin filament to different extents in different regulatory states, thereby affecting the transitions among states that regulate myosin binding and muscle contraction. Development of hypertrophic cardiomyopathy can thus be traced to a defect in the primary mechanism controlling cardiac contraction, switching between different conformations of the thin filament.