Thursday, November 21, 2024
11/21/2024
Sepsis, a dysregulated host response to infection with high morbidity and mortality, is characterized by a systemic inflammatory response and widespread vascular hyperpermeability leading to edema, organ dysfunction, and death. Lung vascular hyperpermeability in sepsis contributes to acute respiratory distress syndrome (ARDS), with no specific prevention or treatment strategies. Disruption of the microvascular endothelial cell (MVEC) barrier is a critical pathological feature of sepsis-induced lung injury driven by circulating inflammatory mediators, oxidants, and proteolytic enzymes. Our group has shown that plasma cell-free hemoglobin (CFH), released during sepsis due to red blood cell fragility, is a mechanistic driver of acute lung injury through induction of lung MVEC hyperpermeability. However, the cellular and molecular mechanisms are unknown. One potential mechanism by which CFH may disrupt the MVEC barrier is through its known ability to oxidize low-density lipoprotein (oxLDL). OxLDL binds and signals through its major endothelial receptor lectin-like oxidized LDL receptor 1 (LOX-1) to cause endothelial dysfunction. LOX-1 activation has been implicated in cardiovascular diseases such as atherosclerosis but its involvement in MVEC hyperpermeability during sepsis is unknown. Our preliminary data from patients with sepsis show that circulating CFH and oxLDL are tightly correlated with each other, MVEC injury markers, and mortality. However, little is known regarding LOX-1 receptor signaling leading to hyperpermeability, especially in the context of sepsis-induced injury to the lung microvasculature. This proposal aims to test the central hypothesis that MVEC hyperpermeability and lung injury during sepsis are mediated through oxidation of LDL by CFH to induce LOX-1 receptor signaling and ectodomain shedding.
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