Summary Phosgene gas has been used as a terrorist weapon, in warfare and has injured many Americans in transportation or industrial accidents. Phosgene targets the lungs, causing severe edema and lung injury after inhalation, with high lethality in exposure victims. Despite these devastating effects, no mechanism-based treatment for phosgene injury has been developed. The renin-angiotensin-aldosterone system (RAAS) plays a key role in cardiopulmonary homeostasis. However, RAAS is dysregulated during acute respiratory distress syndrome (ARDS) contributing to underlying pathophysiology. Pro-resolving mediators that are generated during the inflammation cascade are short-lived due to degradation by an enzyme called soluble epoxide hydrolase (sEH). Several pulmonary studies showed that inhibition of sEH ameliorated the study outcomes. In our preliminary studies, we noted both dysregulation of RAAS and pro-resolving epoxides after phosgene inhalation. We found that administration of angiotensin- converting enzyme (ACE) inhibitors such as Captopril, Enalapril, or Lisinopril improved survival rate, decreased pulmonary protein leak, and diminished bronchoalveolar inflammatory cell counts. Similarly, when soluble epoxide hydrolase inhibitors (sEHIs) were administered to mice after phosgene inhalation, the survival rate significantly improved. Therefore, targeting RAAS and sEH seems to be highly promising. In this application, based on our strong preliminary data, we hypothesize that targeting the RAAS, including angiotensin- converting enzyme (ACE) and aldosterone, and stimulating resolution pathways by administration of soluble epoxide hydrolase inhibitors (sEHIs) post phosgene exposure ameliorates lung injury, leading to decreased morbidity and improved recovery. The following aims are proposed: Aim 1: Screen the efficacy of RAAS modulators and sEHIs in mouse models of phosgene gas-induced lung injury. Aim 2: Determine the pharmacokinetics of the lead drug candidate and test the efficacy in a 48-hour observation model of swine phosgene gas-induced lung injury. Aim 3: Determine therapeutic efficacy of the lead candidate in an extended 28-day observation swine model of phosgene-induced lung injury. Successful completion of the proposed work will provide pivotal information on the development of targeted treatment to protect against phosgene gas-induced lung injuries – a critical unmet need, and will prepare us for Biomedical Research Development Authority (BARDA)-enabling studies and eventual FDA approval under the animal rule.