PROJECT SUMMARY The distressingly high mortality from acute respiratory distress syndrome (ARDS) represents a dramatic loss of quality human life-years. No medicines have yet been developed that treat ARDS, so management remains purely supportive as patients are nursed through their illness in a critical care setting. A key component of this management involves mechanical ventilation. Unfortunately, the stresses and strains of mechanical ventilation can further damage already injured lung tissues, causing lung compliance to decrease and the stresses and strains of mechanical ventilation to increase commensurately. This, in turn, worsens tissue damage in a vicious cycle that is often ultimately fatal. Accordingly, the central premise of this proposal is that managing ARDS requires, above all else, the minimization of VILI. Our prior studies lead to the over-arching hypothesis that the development of ARDS occurs only once repetitive recruitment and derecruitment (RecDer) of lung units initiates an epithelial leak that allows fluid and proteins to begin to accumulate in the airspaces. The consequences of allowing this process to start are dire; surfactant function becomes impaired, surface tension and tissue stresses increase, and the leak worsens in a vicious cycle that accelerates indefinitely. Once underway, this process is difficult to reverse and is exacerbated by over-distension (OD) of the lung tissues, making its avoidance paramount for patients at risk of developing ARDS. Our goal is to comprehensively test this hypothesis both in vitro and in vivo in a range of three relevant model systems: 1) using biofluid mechanics studies we will investigate fundamental interactions that may lead to RecDer, and at the cellular level in vitro we will determine how both OD of lung tissue and repetitive RecDer of lung airspaces act individually and synergistically to damage the airway epithelium in epithelial cell monolayers grown on the inside of compliant tubes subjected to stretch and/or liquid bubble passage, respectively, 2) at the whole lung level in vivo we will determine how over-distension and RecDer lead to leak of proteinaceous fluid into the lung airspaces and cause derangements in lung mechanics and 3) we will determine how VILI can be minimized in a clinically relevant porcine surfactant deactivation model of heterogeneous ARDS subjected to a variety of modes of mechanical ventilation that apply differing relative degrees of tissue over-distention and RecDer. The data collected in Aims 1 and 2 will inform the development of a computational model that predicts how VILI develops over time as a result of the epithelial damage caused by RecDer and the exacerbating influences of overdistension. The model will be tested under clinically relevant conditions in Aim 3. These studies will establish the pathophysiologic understanding upon which personalized approaches to mechanical ventilation that minimize VILI can be developed for individual ARDS patients.