Role of mitochondrial dysfunction in hyperoxia-induced pulmonary vascular endothelial injury

线粒体功能障碍在高氧诱导的肺血管内皮损伤中的作用

基本信息

项目摘要

More than 250,000 veterans are placed on mechanical ventilation annually. These patients often require high fractions of oxygen (hyperoxia) which significantly exacerbates the injury that triggered mechanical ventilation initially. Pulmonary endothelial cells (PECs) are particularly sensitive to hyperoxia, exhibiting increased production rates of mitochondrially-derived reactive oxygen species (mtROS), mitochondrial (mt) dysfunction, pulmonary edema and ultimately increased morbidity/mortality in critically ill patients, but mechanisms are incompletely understood. Cells adapt to stress by increasing both mitochondrial fission and fusion. Our data identify for the first time hyperoxia-enhanced mt-fragmentation in PECs, and decreased expression of mt- fusion and increased expression of mt-fission promoting proteins which underlie the increased mt- fragmentation. In addition, we show that mitochondrial targeted endonuclease repair protein (mt-ENDO-III) protects from hyperoxic PEC loss. Finally, we have demonstrated that inhaled 2% hydrogen gas (H2) can protect against hyperoxia-induced lung injury, and that this protection can be identified by single photon emission computed tomography (SPECT) imaging. The molecular basis of hyperoxia-associated mt- fragmentation and subsequent pulmonary microvascular permeability is the focus of this proposal. Our hypothesis is that hyperoxia-induced pulmonary edema results from mtDNA damage which signals a shift to pro-fission protein expression and mt-fragmentation, leading to increased microvascular permeability and edema. Furthermore, we believe that 2% H2 in atmospheric gases will counteract hyperoxia-evoked pulmonary edema with diminished mtDNA damage and mt-fragmentation. Using novel tools including Dendra- 2 mice, which express a fluorescent protein targeted to the mitochondrial membrane in endothelial cells to quantify mt-fragmentation in intact tissue, recombinant adeno- and lentivirus, siRNA, unique genetically modified rodents, vertical experimental designs from cultured cells to intact animals and human tissue, our work will determine mechanisms linking hyperoxia-induced mtDNA damage, mt-fragmentation and pulmonary edema. Specific Aims: 1) To determine if hyperoxia-induced pulmonary endothelial mtDNA damage modifies expression/activation ratios of specific mt-fission and fusion proteins, thereby enhancing mt-fragmentation, and increasing microvascular permeability. We will use mt-ENDO-III to repair mtDNA damage in cultured PECs and in vivo and measure hyperoxia-induced changes in pro-fission or fusion protein expression, mt-fragmentation, mt-function, monolayer transendothelial electrical resistance (TEER) or filtration coefficient (Kf) as measures of endothelial permeability. 2) To test if pulmonary endothelial mt-fragmentation, independent of mtDNA damage, increases microvascular permeability. Using genetically modified rodents, siRNA and overexpression of pro-fission or fusion protein in cultured PECs and in vivo, we will measure pulmonary endothelial mt-fragmentation, mt-function, and Kf in intact lungs or TEER in cultured PECs. 3) To determine if (i) H2 protects from hyperoxia-induced mtDNA damage, increased mt-fragmentation, or increased microvascular permeability, and (ii) SPECT imaging can identify protection secondary to limited mtDNA damage, diminished mt-fragmentation, or diminished microvascular permeability in vivo. In this translational aim, we will assess the effect of 2% H2 on mtDNA integrity, shifts in pro-fission/fusion proteins, and mt- fragmentation. Genetic manipulations of fission/fusion proteins or ENDO-III will be employed to modify mt- fragmentation, and in vivo SPECT imaging markers of death or oxidoreductive state will identify clinically relevant endpoints associated with changes in pulmonary endothelial mt-fragmentation. Key results will be confirmed in human tissue. This work will provide critical new information about the role of mitochondrial damage in mediating hyperoxia-induced changes in pulmonary microvascular permeability and is expected to lead to mechanism-based approaches to the prevention and treatment of hyperoxia-induced lung disease.
每年有超过 250,000 名退伍军人接受机械通气。这些患者往往需要高 氧气含量(高氧)会显着加剧引发机械通气的损伤 最初。肺内皮细胞 (PEC) 对高氧特别敏感,表现出增加的 线粒体衍生的活性氧 (mtROS) 的产生率、线粒体 (mt) 功能障碍、 肺水肿并最终增加危重患者的发病率/死亡率,但机制是 不完全理解。细胞通过增加线粒体裂变和融合来适应压力。我们的数据 首次鉴定 PEC 中高氧增强的 mt 断裂,以及 mt 表达降低 mt-裂变促进蛋白的融合和表达增加是 mt-裂变增加的基础 碎片化。此外,我们还发现线粒体靶向核酸内切酶修复蛋白(mt-ENDO-III) 防止高氧 PEC 损失。最后,我们证明吸入 2% 氢气 (H2) 可以 防止高氧引起的肺损伤,并且这种保护可以通过单光子来识别 发射计算机断层扫描 (SPECT) 成像。高氧相关线粒体的分子基础 碎裂和随后的肺微血管通透性是该提案的重点。 我们的假设是,高氧诱导的肺水肿是由 mtDNA 损伤引起的,这标志着一种转变 促裂变蛋白表达和 mt 断裂,导致微血管通透性增加 浮肿。此外,我们相信大气中 2% 的 H2 将抵消高氧引起的 肺水肿伴有 mtDNA 损伤和 mt 碎片减少。使用包括 Dendra 在内的新颖工具 2只小鼠,表达针对内皮细胞线粒体膜的荧光蛋白 量化完整组织中的 mt 片段、重组腺病毒和慢病毒、siRNA、遗传上独特的 改良的啮齿动物,从培养细胞到完整动物和人体组织的垂直实验设计,我们的 这项工作将确定高氧诱导的 mtDNA 损伤、mt 断裂和肺损伤之间的联系机制。 浮肿。具体目标:1) 确定高氧诱导的肺内皮 mtDNA 损伤是否会改变 特定 mt 裂变和融合蛋白的表达/激活比率,从而增强 mt 断裂,以及 增加微血管通透性。我们将使用 mt-ENDO-III 来修复培养的 PEC 中的 mtDNA 损伤 体内并测量高氧诱导的裂变或融合蛋白表达、mt 断裂、 mt 函数,单层跨内皮电阻 (TEER) 或过滤系数 (Kf) 作为 内皮通透性的测量。 2) 测试肺内皮细胞碎片是否独立于 mtDNA 损伤,增加微血管通透性。使用转基因啮齿动物、siRNA 和 如果在培养的 PEC 和体内过度表达前裂变或融合蛋白,我们将测量肺 完整肺中的内皮 mt 断裂、mt 功能和 Kf 或培养的 PEC 中的 TEER。 3) 判断是否 (i) H2 可以防止高氧引起的 mtDNA 损伤、mt 断裂增加或 mtDNA 增加 微血管通透性,以及 (ii) SPECT 成像可以识别有限 mtDNA 的继发保护 损伤、mt破碎减少或体内微血管通透性降低。在这个翻译中 目标,我们将评估 2% H2 对 mtDNA 完整性、促裂变/融合蛋白的变化以及 mt- 碎片化。裂变/融合蛋白或 ENDO-III 的基因操作将用于修饰 mt- 碎片,以及死亡或氧化还原状态的体内 SPECT 成像标志物将在临床上进行识别 与肺内皮 mt 碎片变化相关的相关终点。主要结果将是 在人体组织中得到证实。这项工作将提供有关线粒体作用的重要新信息 介导高氧诱导的肺微血管通透性变化的损害,预计 导致基于机制的方法来预防和治疗高氧引起的肺部疾病。

项目成果

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ELIZABETH R JACOBS其他文献

ELIZABETH R JACOBS的其他文献

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{{ truncateString('ELIZABETH R JACOBS', 18)}}的其他基金

Role of mitochondrial dysfunction in hyperoxia-induced pulmonary vascular endothelial injury
线粒体功能障碍在高氧诱导的肺血管内皮损伤中的作用
  • 批准号:
    10455405
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Novel imaging to identify lung mitochondrial injury and predict recovery
识别肺线粒体损伤并预测恢复的新型成像技术
  • 批准号:
    8830999
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Novel imaging to identify lung mitochondrial injury and predict recovery
识别肺线粒体损伤并预测恢复的新型成像技术
  • 批准号:
    8708958
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Novel Diagnostics to Detect Lung Injury
检测肺损伤的新型诊断方法
  • 批准号:
    8543980
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Novel imaging to identify lung mitochondrial injury and predict recovery
识别肺线粒体损伤并预测恢复的新型成像技术
  • 批准号:
    8577599
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Novel Diagnostics to Detect Lung Injury
检测肺损伤的新型诊断方法
  • 批准号:
    8803317
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Novel Diagnostics to Detect Lung Injury
检测肺损伤的新型诊断方法
  • 批准号:
    8680004
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
ROLE OF LEUKOTRIENE B4 METABOLISM IN SEVERE ASTHMA
白三烯 B4 代谢在严重哮喘中的作用
  • 批准号:
    7375111
  • 财政年份:
    2005
  • 资助金额:
    --
  • 项目类别:
Mechanisms of High Flow Induced Vasculopathy
高流量诱发血管病变的机制
  • 批准号:
    7035854
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:
Mechanisms of High Flow Induced Vasculopathy
高流量诱发血管病变的机制
  • 批准号:
    6875027
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:

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Role of mitochondrial dysfunction in hyperoxia-induced pulmonary vascular endothelial injury
线粒体功能障碍在高氧诱导的肺血管内皮损伤中的作用
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    10455405
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