- Pulmonary Capillary Wedge Pressure <18mmHg or no clinical evidence of increased left atrial pressure Although a broad range of risk factors for ALI have been described, those that account for the majority of cases include: sepsis, pneumonia, trauma, and aspiration. It is well established that severe trauma is recognized as a precipitating cause of ALI. Recent studies have demonstrated that the incidence of acute lung injury (ALI) is much higher than previously thought, with an estimated age-adjusted incidence of 86 per 100,000 persons per year, resulting in an estimated ~190,000 cases annually in the US. The clinical and health care system impact of ALI is substantial, with an estimated 2,154,000 intensive care unit (ICU) days, 3,622,000 hospital days, and 75,000 deaths in 2000, and is expected to grow significantly given the marked age-related incidence and the aging population. Although general improvements in ICU care over the last 2 decades have led to a trend towards lower mortality due to certain ALI-associated risk factors (trauma, aspiration), the most common causes of ALI, sepsis and pneumonia, remain associated with high mortality rates of ~25-35%. Mortality in ALI is most commonly due to secondary infections/sepsis and multiorgan system failure rather than primary respiratory failure due to hypoxemia, highlighting the systemic nature of ALI. Even among initial survivors of ALI, substantial pulmonary and nonpulmonary functional impairment remains for months to years. Specifically, a proportion of those who survive the initial insult are at risk for prolonged mechanical ventilation and ICU/hospital stay, and the risk factors remain poorly defined. It has been hypothesized that a "2nd hit" may predispose certain patients to greater morbidity in this setting. Despite intensive basic and clinical investigation, only a single intervention (low-tidal volume ["lung protective"] ventilation) is generally accepted to decrease mortality in ALI, while multiple other strategies have failed to improve survival either in early clinical studies or definitive efficacy trials. Thus, given the high incidence and continued substantial clinical impact of ALI despite improvements in general medical/ICU care, and limited proven options other than lung-protective ventilation, new approaches to understanding the pathophysiology and identifying novel targets for intervention in ALI are a high priority.