When asked “how do we treat the pulmonary edema of a patient with hypoxemic respiratory failure?” house-staff and attending physicians commonly respond:“diuretics combined with sodium and fluid restriction.” This response reflects a bias in our therapeutic strategies for patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) to decrease alveolar edema formation. Although it is well established that increased permeability of the alveolo–capillary barrier favors edema formation, a less recognized fact is that the balance between edema formation and edema clearance is of critical importance for the patient to recover from lung injury. In this issue of the Journal (pp. 1376–1383) Ware and Matthay (1) emphasize the importance of impaired lung edema clearance in determining outcome in patients with ALI/ARDS and report that patients with impaired ability to clear edema had worse outcomes. The rationale for this study stems from previous clinical reports and animal studies describing the mechanisms by which alveolar fluid reabsorption is impaired during lung injury (2–5). In the present study, Ware and Matthay evaluated edema fluid from 79 patients obtained by aspirating secretions from the endotracheal tube via a small-bore catheter. Because protein removal from the airspaces is slower than fluid, the estimate of fluid clearance was assessed by measuring edema fluid protein concentration over time, where the magnitude of protein change equated the rate of fluid clearance. Ware and Matthay found that alveolar fluid clearance was impaired in a majority of ARDS patients, and clearance was impaired in more patients with sepsis as the underlying cause of ARDS. Patients with more rapid edema clearance rates had a shorter duration of mechanical ventilation and lower mortality (1). These findings contrast with data from patients with hydrostatic pulmonary edema where the majority (75%) of patients had normal levels of clearance and only a minority had impaired ability to clear edema (6). Importantly, patients with ALI/ARDS and maximal levels of alveolar fluid clearance had better outcomes. Almost 20 years ago it was first reported that alveolar fluid clearance was effected by active Na transport (7). Clearance mechanisms differ from mechanisms regulating edema formation, where changes in pulmonary filtration coefficient, hydrostatic and oncotic pressure gradients regulate the extent of edema formation. Alveolar fluid clearance is regulated by active Na transport where Na moves vectorially across the alveolar epithelium mostly via apical sodium channels and basolaterally located Na, K-ATPase (Na pump) with water following isosmotically into the interstitium and the pulmonary circulation (8). There is accumulating evidence, mostly from animal models of lung injury, that increasing sodium transport by up-regulating alveolar epithelial Na channels and Na pumps increases lung edema clearance (2, 5). Specifically, several reports have demonstrated that in models of lung injury catecholamines such as terbutaline, isoproterenol, dobutamine, and dopamine up-regulate the function of Na channels and Na, K-ATPase resulting in increased alveolar fluid reabsorption (2, 3, 5). This effect is rapid. Increases in lung edema clearance are observed within 15 min of treatment. Catecholamines regulate the recruitment of functional Na pumps from intracellular compartments, which are inserted into the plasma membrane of alveolar epithelial cells within minutes of dopamine or isoproterenol stimulation (9). These effects are dependent on the dynamic interaction between intracellular protein-transporting vesicles and the microtubules …