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.

项目摘要 /摘要 内毒素血症和败血症发生的肺衰竭会引起广泛的肺血管内皮损伤 不受限制地涌入炎性细胞，例如中性粒细胞和巨噬细胞。这种适应不良的炎症 反应超过了肺的修复能力，导致严重的炎症性肺损伤和低氧血症。 该提案着重于适应不良炎症的基本放大机制 肺内皮的激活。我们的中心假设是对威胁信号的炎症反应此类 作为细菌脂多糖（LPS）和快速释放对内皮质膜的最初违反 线粒体通过受伤的线粒体大量进入细胞质的线粒体DNA，并急性扩增炎症 反应，因此是急性肺损伤（ALI）进展的必不可少的前馈机制。目标 1，我们将确定最近鉴定出的穿孔毒素D介导的机制 内皮质膜孔的形成和K+外排离子通道的激活机制 我们最近确定的Twik2。我们将解决扩增K+外排在严重程度和 内皮NLRP3炎性体激活和暴发性肺损伤的速度。在AIM 2中，我们将定义 另一个至关重要的扩增机制，是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，这也可能在灾难性上 通过激活I型干扰素信号传导的放大肺损伤。这些机械驱动的研究将利用 遗传小鼠模型（我们实验室中的内皮特异性敲除模型）以及全面的成像， 电生理和生理方法，因此提供了识别新内皮的框架 诱导肺血管损伤和ALI的扩增炎症机制。我们将阐明如何 可以针对途径来减少组织损伤并改善生存率。