Lung Injury Research
The overall goal of our work in lung injury is to improve the outcome for patients requiring mechanical ventilation by preventing the occurrence of ventilator-induced lung injury (VILI). VILI is a major concern in the ventilation of patients suffering from acute respiratory distress syndrome, which affects as many as 150,000 people in the United States annually, and is associated with mortality of greater than 50%. The working hypothesis in our laboratory is that the alveolar epithelium, which provides the majority of resistance to fluid transport across the blood-gas barrier, is injured by large static and dynamic deformations which occur during mechanical ventilation of diseased lungs, and that this injury is critical in the development of VILI. Our lab created and validated a novel in vitro cell culture preparation of primary epithelial cells seeded on a highly elastic membrane, which we deform in a uniform manner at rates and magnitudes seen in vivo. We demonstrated that epithelial stretch magnitude and rate are correlated with lung fluid balance and permeability, suggesting that over-distension of airspaces should be avoided. Our lab determined deformation strategies to reduce cell mortality and dysfunction, and correlated these in vitro findings with clinical data. In addition we have identified molecular injury signaling pathways that offer potential avenues for pharmacological interventions to prevent or ameliorate VILI in those circumstances when larger lung inflations must be employed to provide sufficient gas exchange. Together the lab's experimental studies and mathematical models address the long-term goal of designing safer, more effective mechanical ventilation maneuvers and new intervention strategies to prevent acute VILI due to epithelial over-distension.
Primary rat type 1 like alveolar epithelial cell monolayer stained for F-actin (RED), zonula occludens protein 1 (ZO-1, GREEN), dapi stained DNA (BLUE)