Genetic Factors Impacting Therapy in Acute Lung Injury/Acute Respiratory Distress Syndrome

Acute lung injury (ALI) and its most severe form the acute respiratory distress syndrome occur in patients who have a predisposing severe inflammatory insult to the lung. Most often ALI is due to sepsis from bacterial infection, but ALI can occur with any infection and with noninfectious insults such as severe trauma, acute pancreatitis, aspiration, and near-drowning. After any of these insults, the interindividual risk of progression to ALI and the risk of death remain difficult to predict. Our inability to predict an individual's susceptibility to acute lung injury has long suggested that genetic factors influence ALI risk. There is substantial evidence for heritable predispositions to severe infections and an emerging body of literature implicating genetic factors in ALI pathogenesis. A paradigm is emerging that the genetic risk for ALI can be best understood in terms of factors that control 3 overlapping stages of ALI pathogenesis: risk for the acquisition of a predisposing condition (such as a severe pneumonia), risk for progression to lung injury during systemic inflammatory states (such as severe sepsis), and risk for failure of endogenous mechanisms to resolve the lung injury. The evidence supporting this paradigm is herein reviewed, along with potential treatment strategies that could be directed by knowledge of specific genetic factors in an individual patient.