Project Summary The adult lung continues to amaze in terms of its complexity and function from the discovery of new cell types to the understanding of new functions of existing cells and molecular pathways operating during homeostasis and injury. Never has lung biology received more attention as during the current COVID-19 pandemic where fundamental studies in lung immunobiology are urgently needed to advance therapeutic development to address unmet need in acute lung injury and the acute respiratory distress syndrome (ARDS). For the past 15 years, we have studied lung biology at the intersection of innate immunity and hematology, which are core components of the NHLBI’s mission. Facilitated by technical development in the intravital imaging of the mouse lung and by advanced transplantation techniques, we have made fundamental discoveries in this area in the normal and injured lung that will serve as the basis of the proposed studies in this application. To advance our understanding of lung injury mechanisms, we will use established models of sterile and pathogen-induced lung injury and extant ARDS biorepositories developed under previous funding to continue our studies of the contribution of platelets, neutrophils, and neutrophil extracellular traps (NETs) to disease pathogenesis. These studies will include mechanisms by which antibodies trigger lung injury after blood transfusions or after solid organ transplantation including the development of novel models of injury and therapeutic targeting. Within this theme, we will continue studies on distinct populations of megakaryocytes in the adult lung and their roles in platelet biogenesis and lung immunity. We will explore the hematopoietic potential of the lung by testing the hypothesis that the human lung contains significant numbers of hematopoietic progenitors that may uniquely contribute to hematopoiesis in homeostasis and injury and after hematopoietic stem cell transplantation. The environment at UCSF includes established collaborations and accessibility to advanced Cores that will enable this program of lung biology to accelerate discoveries under this funding mechanism and move the field forward.