Sepsis patients who exhibit pulmonary vascular injury and high mortality often suffer from platelet depletion (i.e. thrombocytopenia) and severe pulmonary thrombosis, but the beneficial impact of anti-coagulant therapy in clinical trials of sepsis is unconvincing. Despite recent advances in defining the pathogenesis of sepsis-induced lung injury, including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), there are currently no effective pharmacological or cell-based treatments for the disease. A better understanding of the role of pulmonary thrombosis in sepsis-induced lung injury could lead to the development of novel treatments for ALI/ARDS. My preliminary studies show that genetic thrombocytopenia reduces pulmonary thrombosis and increases sepsis-induced lung injury, which can be rescued by induction of a mild and harmless level of pulmonary thrombosis. Furthermore, a mild level of pulmonary thrombosis can be induced to protect against sepsis-induced lung injury in wild type mice, while an excessive level of pulmonary thrombosis worsens injury. My preliminary studies also show that the opposing effects of diminished or excessive versus mild PT on sepsis-induced lung injury are associated with changes in endothelial apoptosis, and that the protective impact of mild pulmonary thrombosis on sepsis-induced lung injury is dependent on hypoxia-inducible factor (HIF) 1a and associated with reduced endothelial apoptosis. In this project, I will test the novel hypothesis that while diminished or excessive pulmonary thrombosis increases sepsis-induced lung injury, a mild and harmless level of pulmonary thrombosis conversely reduces sepsis-induced lung injury via increases in endothelial cell survival factors and decreased endothelial apoptosis. The key aims of the project are to determine whether pulmonary thrombosis regulates the severity of sepsis-induced lung injury and to therapeutically stimulate the signalling pathway downstream of mild pulmonary thrombosis to decrease pulmonary endothelial apoptosis and reduce ALI. These studies will identify a novel signalling pathway that can be induced via mild pulmonary thrombosis to increase endothelial viability and reduce sepsis-induced lung injury. These studies using mouse models of thrombocytopenia, pulmonary thrombosis, and sepsis, and integrated pharmacological, cellular, and molecular biology approaches, could ultimately contribute to the development of new therapies against ALI/ARDS.
|Program type||Career Development Award|
|Effective start/end date||04/01/2019 → 09/30/2022|