Identifying Novel Roles and the Therapeutic Potential of the Thrombin Receptor Protease Activated Receptor-1 (PAR1) in Lung Lymphatic Function and Acute Respiratory Distress Syndrome - Project Abstract Acute Respiratory Distress Syndrome (ARDS) is a devastating disease with high morbidity and mortality. The COVID-19 pandemic and the yearly toll of viral and bacterial pneumonia underscore the urgent need for a mechanistic understanding of ARDS that would lead to new therapies. ARDS is characterized by a prothrombotic state and activation of the thrombin receptor protease activated receptor 1 (PAR1). PAR1 is perhaps the most important mediator of inflammation and coagulation in ARDS, as it coordinates the interplay between platelets, endothelial cells, and the immune response. However, targeting PAR1 therapeutically has thus far been unsuccessful, highlighting our knowledge gaps in understanding the pleiotropic roles of this critical receptor. The premise of proposal is that PAR1 plays a previously unappreciated role in the lymphatic vasculature in ARDS that offers a novel therapeutic strategy to prevent lung injury. The lymphatic vasculature mediates the inflammatory response of the lung through both fluid drainage and trafficking of immune cells. However, the molecular pathways that drive these functions have not been fully uncovered. Lymphatics have specialized endothelial cell junctions that mediate fluid and cell uptake into the vessel lumen. Loss of these permeable ‘button’ junctions impairs lymphatic function by preventing the drainage and cell trafficking function of these vessels. Using mouse models, we have found that PAR1 is necessary for button junction formation during lung injury. Lymphatic-specific loss of PAR1 leads to immune cell accumulation and worse lung injury, which our studies suggest is due to loss of button junctions that promote lymphatic function. These data point to a previously unknown role of PAR1 in lung injury that improves lymphatic drainage and promotes resolution of inflammation. In this proposal, we will test the hypothesis that PAR1 is necessary for lymphatic buttons and function (Aim 1), that thrombin-mediated PAR1 signaling in lymphatics is protective during lung injury due to its role in promoting lymphatic buttons and drainage (Aim 2), and that agonists of PAR1 that promote beneficial PAR1 signaling in lymphatics while persevering blood vessel function are a novel therapeutic strategy for ARDS (Aim 3). When completed these studies will result in an entirely new paradigm for the pathogenesis of ARDS by uncovering a link between PAR1, lymphatic function, and the inflammatory response, leading to a novel therapeutic strategy for this devastating disease.
