Acute lung injury (ALI) is common in critically ill patients, and there has been a great deal of interest in the cellular and molecular mechanisms linking mechanical ventilation with ALI. Although it is possible to ventilate patients with normal lungs for prolonged periods of time without causing lung injury, a landmark controlled randomized clinical trial in critically ill patients with ALI showed that mechanical ventilation with a lung protective strategy improves outcome as compared with conventional mechanical ventilation (1). This trial was based on a series of studies in animals and humans suggesting that mechanical ventilation could injure the lungs, as measured by a number of different parameters (2, 3). In a separate study of humans with ALI, a lung protective strategy reduced cellular and biochemical parameters of the inflammatory response in the lungs, suggesting a key link between the mode of mechanical ventilation and inflammation observed in the lungs (4). The consistent association between polymorphonuclear neutrophils (PMNs) and lung injury in humans and animal models, and the propensity of PMNs and their products to cause tissue injury in experimental systems, led to the conclusion that PMNs have an important causative role in ALI (5, 6). Neutrophil depletion is protective in many animal models of ALI, and blocking the major PMN chemoattractant, IL-8, protects rabbits from lung injury and death following severe acid aspiration (pH 1.5)(7). Yet the results of these studies leave some questions unanswered, because none of the models closely simulate the events that occur in the injured lungs of humans. Although direct studies in humans are very limited, PMNs migrate into normal human lungs in response to an intra-alveolar chemoattractant without causing injury, and without undergoing significant degranulation (8). In addition, studies using G-CSF to augment host defenses in humans with severe pneumonia and sepsis showed that increasing the circulating PMN count to high levels was not associated with worsening clinical manifestations of lung injury (9, 10). Similarly, studies in sheep using the bidirectional movement of alveolar and vascular tracers showed that large numbers of PMNs migrate into the lungs in response to bacterial lipopolysaccharide without injuring the critical epithelial barrier of the lungs, even though endothelial permeability is increased (11). Careful ultrastructural studies in rabbits and mice have shown that PMNs migrate through specialized channels in endothelial and epithelial basement membranes and into the alveolar spaces in areas of streptococcal pneumonia without causing apparent damage to these barriers (12). Taking a different approach, a study of the metabolic activity of lung PMNs in rabbits with streptococcal pneumonia showed that the most metabolically active PMNs are in the alveolar spaces, and not in the microvasculature or the interstitium, suggesting that the major activation events occur in the alveolar spaces in response to bacteria, and not during migration (13).