Sunday, April 2, 2023
4/2/2023
PROJECT SUMMARY / ABSTRACT Lung failure from endotoxemia and sepsis induces widespread and often rapid lung vascular endothelial injury due to unfettered influx of inflammatory cells such as neutrophils and macrophages. This maladaptive inflammatory response outpaces the reparative capacity of lungs, resulting in profound inflammatory lung injury and hypoxemia. This proposal focuses on fundamental amplification mechanisms underlying the maladaptive inflammatory activation of the lung endothelium. Our central hypothesis is that the inflammatory response to threat signals such as the initial breaching of the endothelial plasma membrane by bacterial lipopolysaccharide (LPS) and rapid release of mitochondrial DNA by the injured mitochondria into the cytosol massively and acutely amplifies the inflammatory response and thus serves as essential feed-forward mechanisms for progression of acute lung injury (ALI). In Aim 1, we will determine the mechanisms by which the recently identified perforin Gasdermin D mediates endothelial plasma membrane pore formation and the mechanisms of activation of the K+ efflux ion channel TWIK2 that we have recently identified. We will address the role of amplifying K+ efflux on the severity and rapidity of endothelial NLRP3 inflammasome activation and fulminant lung injury. In Aim 2, we will define another crucial amplification mechanism, the potentially important role of Gasdermin D-mediated mitochondrial (mt) membrane pore formation and the release of mtDNA, which may also catastrophically amplifiy lung injury via activation of Type I interferon signaling. These mechanistically driven studies will utilize genetic mouse models (endothelial specific knockout models in our labs) as well as comprehensive imaging, electrophysiological and physiological approaches and thus provide the framework for identifying novel endothelial amplification inflammatory mechanisms that induce lung vascular injury and ALI. We will elucidate how these pathways can be targeted to reduce tissue damage and improve survival.
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