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: 10543845
• 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/10543845
• 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 Survival; 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; Macrophage; 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; Role; Sepsis; Severities; Signal Pathway; Signal Transduction; Stimulator of Interferon Genes; System; Testing; Tissues; Vascular Endothelium; cell regeneration; cytokine; endothelial regeneration; fighting; immune activation; improved; intravital imaging; lung failure; lung imaging; lung injury; lung vascular injury; 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.

项目概要/摘要 内毒素血症和脓毒症引起的肺衰竭会引起广泛且往往是快速的肺血管内皮损伤 导致中性粒细胞和巨噬细胞等炎症细胞不受限制地流入。这种适应不良的炎症 反应速度超过了肺部的修复能力，导致严重的炎症性肺损伤和低氧血症。 该提案重点关注适应不良炎症的基本放大机制 肺内皮细胞的活化。我们的中心假设是，对威胁的炎症反应发出这样的信号： 作为细菌脂多糖 (LPS) 最初破坏内皮质膜并快速释放 受损线粒体将线粒体 DNA 大量进入细胞质并急剧放大炎症 反应，因此成为急性肺损伤（ALI）进展的重要前馈机制。瞄准 1，我们将确定最近鉴定的穿孔素 Gasdermin D 介导的机制 内皮质膜孔的形成和 K+ 流出离子通道的激活机制 我们最近发现了 TWIK2。我们将讨论放大 K+ 流出对严重程度和影响的作用。 内皮 NLRP3 炎性体激活和暴发性肺损伤的速度。在目标 2 中，我们将定义 另一个重要的放大机制，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，这也可能造成灾难性的后果 通过激活 I 型干扰素信号传导放大肺损伤。这些机械驱动的研究将利用 遗传小鼠模型（我们实验室的内皮特异性敲除模型）以及综合成像， 电生理学和生理学方法，从而为识别新型内皮细胞提供了框架 放大诱导肺血管损伤和 ALI 的炎症机制。我们将阐明这些如何 可以有针对性地减少组织损伤并提高生存率。