Amplification Mechanisms of Lung Endothelial Inflammation During Acute Lung Injury

急性肺损伤期间肺内皮炎症的放大机制

• 批准号: 10435435
• 负责人: Asrar B. Malik
• 金额: $ 57.46万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435435
• 关键词: Acute; Acute Lung Injury; Address; Amplifiers; Anti-Inflammatory Agents; Antibiotics; Bacteria; Bacterial DNA; Bacterial Infections; Binding; Blood Circulation; Blood Vessels; Caspase; Cell Death; Cell membrane; Cells; Cessation of life; Complication; Cytosol; DNA; DNA Damage; Data; Disease Progression; Electrophysiology (science); Endothelial Cells; Endothelium; Endotoxemia; Genetic; Host Defense; Hypoxemia; Image; Immune; Immune response; Immune system; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferon Type I; Interleukin-1 beta; Intervention; Ion Channel; Ions; Knock-out; Lead; Lipopolysaccharides; LoxP-flanked allele; Lung; Lung Capacity; Mediating; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Multiple Organ Failure; N-terminal; Natural regeneration; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Physiological; Proteins; Regenerative capacity; Research; Respiratory Failure; Role; Sepsis; Severities; Signal Pathway; Signal Transduction; Stimulator of Interferon Genes; System; Testing; Tissues; Vascular Endothelium; base; cell regeneration; cytokine; endothelial regeneration; fighting; immune activation; improved; intravital imaging; lung imaging; lung injury; lung vascular injury; macrophage; microvesicles; mitochondrial membrane; mortality; mouse model; neutrophil; novel; novel therapeutic intervention; pathogen; perforin; polymicrobial sepsis; prevent; programs; reparative capacity; response; two-photon; viral DNA

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.

项目总结/摘要 内毒素血症和脓毒症引起的肺衰竭可引起广泛且通常快速的肺血管内皮损伤， 炎症细胞如中性粒细胞和巨噬细胞的不受限制的流入。这种适应不良的炎症 反应速度超过肺的修复能力，导致严重的炎性肺损伤和低氧血症。 这项建议的重点是基础放大机制的适应不良的炎症反应， 激活肺内皮。我们的中心假设是，对威胁的炎症反应发出这样的信号， 由于细菌脂多糖（LPS）最初破坏内皮细胞质膜， 损伤的线粒体大量释放线粒体DNA进入胞质，并急性放大炎症反应。 反应，并因此作为重要的前馈机制的急性肺损伤（ALI）的进展。在Aim中 1，我们将确定最近发现的穿孔素Gasdermin D介导 内皮细胞质膜孔的形成和K+外排离子通道的激活机制 我们最近发现的TWIK 2。我们将讨论放大K+外流对严重性的作用， 内皮NLRP 3炎性体活化和暴发性肺损伤的快速性。在目标2中，我们定义 另一个关键的扩增机制，Gasdermin D介导的潜在重要作用， 线粒体（mt）膜孔的形成和mtDNA的释放，这也可能是灾难性的 通过激活I型干扰素信号传导减轻肺损伤。这些机械驱动的研究将利用 遗传小鼠模型（我们实验室中的内皮特异性敲除模型）以及全面成像， 因此提供了用于鉴定新的内皮细胞的框架， 放大炎症机制，诱导肺血管损伤和ALI。我们将阐明这些 可以靶向这些通路以减少组织损伤并提高存活率。