PROJECT SUMMARY Acute Respiratory distress syndrome (ARDS) is a life-threatening condition caused by widespread pulmonary inflammation leading to lung injury. ARDS has a mortality that can be higher than 40% and is the main cause of death from COVID-19. Although necessary to support life, mechanical ventilation worsens ARDS. While computed tomography (CT) is capable of identifying characteristic abnormal airspace mechanics, the pulmonary circulation is also altered in ARDS, with profound dysregulation of lung perfusion resulting in regional elevations of blood flow and volume. Such misdistribution may significantly impact the trajectory of lung injury. In animal studies, ventilated lungs suffered from stress-failure of the capillary barrier when perfused at higher blood flows and pressures, resulting in more edema. Regions of the lung with elevated perfusion may therefore be at risk of worse injury. The pulmonary circulation is significantly understudied in ARDS due to the paucity of accurate and non-invasive instruments to visualize perfusion in vivo. This proposal addresses the need to elucidate the fundamental contribution of the pulmonary circulation to ARDS trajectory. We intend to develop a comprehensive imaging approach to characterize lung perfusion and direct treatment. We will leverage our expertise with two imaging modalities: a) dynamic contrast enhanced (DCE) and dual energy CT (DECT), which map pulmonary blood flow and volume with high resolution; b) electrical impedance tomography (EIT), a bedside technique that allows rapid and frequent assessments of pulmonary perfusion without moving patients to a scanner. We will use these techniques in animal and human studies to test our hypothesis that protecting the capillary barrier and manipulating pulmonary perfusion to decrease capillary stress failure attenuates ARDS progression. In a ventilated swine model of ARDS, we will demonstrate that reducing the heterogeneity of pulmonary perfusion mitigates lung injury using two treatments that redistribute pulmonary blood flow and volume: selective vasodilation with inhaled nitric oxide (iNO) and prone ventilation. We will match regional changes in perfusion and inflation with the subsequent progression of lung injury. We will then show that protecting the pulmonary capillaries in vulnerable lung regions decreases injury using Imatinib, a drug that preserves endothelial integrity, in our swine model. Finally, after refining our translational imaging pipeline, we will perform proof-of-principle studies in human ARDS using DECT and EIT to assess individual patient responses to iNO and prone ventilation, aiming to integrate such information into clinical decision-making. This proposal will demonstrate that it is possible to non-invasively assess pulmonary perfusion in order to guide ARDS treatment. Shifting the focus from airspace mechanics to a more comprehensive management of both lung perfusion and ventilation, the proposed approach will cons...