ABSTRACT: The Pre-Clinical models of acute lung injury Core (Core C) is designed to provide PPG investigators with rigorously defined and reproducible rat and porcine models of combined acute respiratory distress syndrome (ARDS) and ventilation-induced lung injury (VILI). The unprecedented COVID-19 pandemic with high mortality rates of COVID-19-induced ARDS has dramatically raised the demand for a deeper understanding of the critical role of the EC cytoskeleton in the pathobiology of ARDS and VILI and deepened the unmet need for FDA- approved ARDS pharmacotherapies. Core C will comprehensively generate, manage, and provide all animal- related experiments, resources, and expertise to all four projects by accomplishing five specific aims. Specific Aim #1 provides a complete range of expertise, training, equipment, and data analysis tools to extensively study and characterize the role of the cytoskeleton in preclinical models of lung injury. Core C will employ the state-of- the-art techniques to a) characterize the role of the cytoskeleton in regulating lung endothelial cell (EC) barrier function, b) determine the effects of specific interventions to provide insight into the efficacy and mechanisms of novel therapeutic strategies, and c) facilitate the translation of basic research to clinical interventions. Specific Aim #2 is to house and maintain rats and pigs utilized in this PPG. Specific Aim #3 examines selective pharmacological agonists, antagonists, or monoclonal antibodies for PPG-targeted effectors, cytoskeletal, and focal adhesion proteins as potential therapeutic strategies and approaches for ARDS/VILI models. Specific Aim #4 provides rigorously performed, protocol-driven performance of specific experimental strategies involving preclinical models of ARDS/VILI. Specific Aim #5 is to perform highly detailed studies and provide high quality genomic, biochemical phenotyping (BAL protein, BAL cell count/cellularity, lung tissue albumin levels, assessment of lung capillary leakage by Evans Blue dye (EBD), quantitative lung histology, and immunohistochemistry). Also, Core C provides physiologic measurements (static and dynamic compliance of the respiratory system, oxygenation index), radiographic and ultrasound images to support these studies. The magnitude of ARDS and recovery responses will be determined by generating the acute lung injury severity score (ALISS). Core C will perform lung injury assessment, provide plasma, and tissue samples to individual projects for specific assays (including immunohistochemistry and western blot analysis). Our work in Core C will provide full preclinical support to all four projects and provide the tools they need to get a greater mechanistic understanding of lung EC barrier regulation while driving therapeutic developments directed toward restoring the integrity of the injured pulmonary circulation, thereby reducing ARDS mortality.