Acute lung injury (ALI) represents a continuum of pathologies that causes alveolar epithelial and endothelial cell disruption or dysfunction, which leads to immediate or delayed edema and a significant disturbance in surfactant homeostasis. Acute respiratory distress syndrome (ARDS) is the most severe clinical manifestation of ALI. ARDS is a debilitating and often fatal condition that can result from numerous seemingly unrelated direct or indirect insults. Mortality rates associated with ALI/ARDS have changed little over the last several decades and remain ~30–40%. Because the past candidate-gene approaches have not led to reliable pharmacological treatments, the current treatment strategies primarily depend on supportive measures (e.g., patient repositioning and improved oxygenation strategies) to affect outcome.
The Prows Lab has taken a much different approach to study this intractable disease. Because mortality is the most critical endpoint to make an impact, we have used this trait as the endpoint measure in a large-scale genetics approach in mice to identify critical factors affecting differential ALI susceptibility. A genetics approach is not feasible in humans, because ALI/ARDS does not run in families and inciting agents and level of exposures differ among cases. To remove preconceived biases as to which genes or factors are important in survival, we use quantitative trait locus (QTL) analysis—a reverse genetics approach that does not depend on a priori data or information—to steer us towards the responsible genes.