(A) ALI leads to lung endothelial and epithelial injury, increased permeability of the alveolar-capillary barrier, flooding of the airspace with protein-rich pulmonary edema fluid, activation of alveolar macrophages with release of proinflammatory chemokines and cytokines, enhanced neutrophil migration and activation, and fibrin deposition (hyaline membranes). (B) If the injured lung is ventilated with high tidal volumes and high inflation pressures (high-stretch ventilation), then lung injury is exacerbated, with increased lung endothelial and epithelial injury and/or necrosis, enhanced neutrophil margination, release of injurious neutrophil products such as proteases and oxidants, increased release of proinflammatory cytokines from alveolar macrophages and the lung epithelium, increased fibrin deposition, and increased hyaline membrane formation. Injurious mechanical ventilation can also impair alveolar fluid clearance (AFC) mechanisms. (C) In contrast, a protective ventilatory strategy (low-stretch ventilation) can limit further lung endothelial and epithelial injury, reduce the release of proinflammatory cytokines, and enhance alveolar fluid clearance through the active transport of sodium and chloride across the alveolar epithelium (see Figure 4), thereby reducing the quantity of pulmonary edema and allowing endothelial and epithelial repair to occur. Epithelial repair occurs through migration, proliferation, and differentiation of alveolar epithelial type II cells to repopulate the denuded basement membrane. Acute inflammation resolves through apoptosis of neutrophils, which are phagocytosed by alveolar macrophages (see Figure 4).