Modulation of inflammation in aging lung

调节衰老肺部的炎症

• 批准号: 10557197
• 负责人: Konstantin Birukov
• 金额: $ 38.46万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557197
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Adult; Age; Aging; Animal Model; Anti-Inflammatory Agents; Antibiotic Resistance; Antibiotic Therapy; Antioxidants; Bacterial Infections; Biological; Cell Death; Cell Death Signaling Process; Cell membrane; Cell model; Cells; Cessation of life; Choline; Clinical; Clinical Treatment; Defense Mechanisms; Deterioration; Endothelium; Equilibrium; Event; Exhibits; Family; Functional disorder; Generations; Genetic; Image; Impairment; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Intercept; Interleukin-1 beta; Intervention; Lead; Length; Lipid Peroxidation; Lung; Lung diseases; Lung infections; Macrophage; Maps; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Mus; Older Population; Organ; Organism; Oxidation-Reduction; Oxidative Stress; Pathogenicity; Pathologic; Pathway interactions; Permeability; Phospholipids; Pilot Projects; Pneumonia; Populations at Risk; Predisposition; Process; Production; Property; Pulmonary Inflammation; Reaction; Reactive Oxygen Species; Recovery; Recurrence; Role; Sampling; Severities; Signal Pathway; Signal Transduction; Staphylococcus aureus; Syndrome; System; TNFRSF10B gene; TXNIP gene; Technology; Testing; Time; Tissues; Up-Regulation; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vulnerable Populations; age related; aging population; alveolar epithelium; clinically relevant; injury recovery; lung injury; methicillin resistant Staphylococcus aureus; mouse model; neutrophil; novel therapeutics; older patient; oxidant stress; oxidation; particle; pathogenic bacteria; pharmacologic; pre-clinical; prevent; protein expression; protocol development; pulmonary function; respiratory; response; translational study; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adult; Age; Aging; Animal Model; Anti-Inflammatory Agents; Antibiotic Resistance; Antibiotic Therapy; Antioxidants; Bacterial Infections; Biological; Cell Death; Cell Death Signaling Process; Cell membrane; Cell model; Cells; Cessation of life; Choline; Clinical; Clinical Treatment; Defense Mechanisms; Deterioration; Endothelium; Equilibrium; Event; Exhibits; Family; Functional disorder; Generations; Genetic; Image; Impairment; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Intercept; Interleukin-1 beta; Intervention; Lead; Length; Lipid Peroxidation; Lung; Lung diseases; Lung infections; Macrophage; Maps; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Mus; Older Population; Organ; Organism; Oxidation-Reduction; Oxidative Stress; Pathogenicity; Pathologic; Pathway interactions; Permeability; Phospholipids; Pilot Projects; Pneumonia; Populations at Risk; Predisposition; Process; Production; Property; Pulmonary Inflammation; Reaction; Reactive Oxygen Species; Recovery; Recurrence; Role; Sampling; Severities; Signal Pathway; Signal Transduction; Staphylococcus aureus; Syndrome; System; TNFRSF10B gene; TXNIP gene; Technology; Testing; Time; Tissues; Up-Regulation; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vulnerable Populations; age related; aging population; alveolar epithelium; clinically relevant; injury recovery; lung injury; methicillin resistant Staphylococcus aureus; mouse model; neutrophil; novel therapeutics; older patient; oxidant stress; oxidation; particle; pathogenic bacteria; pharmacologic; pre-clinical; prevent; protein expression; protocol development; pulmonary function; respiratory; response; translational study

Project Summary/Abstract Modulation of inflammation in aging lung Increased severity and delayed recovery of pneumonia and associated lung injury in older patients represents a serious threat for this vulnerable population, but molecular mechanisms of this age-dependent phenomenon remain poorly understood. As antioxidant defense mechanisms in aging organism become impaired, increased production of reactive oxygen species during inflammation may cause exaggerated oxidant stress. In turn, increased oxidation of the cell membrane and circulating phospholipids leads to generation of a family of fragmented products of phospholipid oxidation (FPL), which may exhibit deleterious effects on the host cells. In pilot studies we used a mass spectrometry approach and identified several FPL species with highest levels found in the inflamed aging lungs. Our pilot studies suggest that age-dependent elevation of FPLs augments lung dysfunction and impairs vascular endothelial cell (EC) barrier in cell and animal models of acute lung injury (ALI). We hypothesize that increased generation of FPL in the aging population as a result of dysregulated redox balance exacerbates lung inflammation and vascular dysfunction via direct effects on endothelial permeability, FPL-induced activation of thioredoxin interacting protein, and activation of cell death mechanisms leading to impaired ALI recovery. Using clinically relevant models of ALI induced by live antibiotic- resistant Staphylococcus aureus (S. au, USA300 CA-MRSA clinical strain 923) or heat-killed S. au recapitulating clinical treatment of antibiotics-sensitive strains, this translational study will employ for the first time the quantitative mass spectrometry approach to identify specific FPL elevated in the aging lung during ALI and test their role in exacerbation of lung inflammation and barrier dysfunction. LC-MS-MS and imaging MS technologies will be applied to preclinical mouse models of inflammatory lung injury to identify the spectrum of FPL produced in the inflamed aging lungs, generate the maps of FPL distribution in the lung samples and relate them to topography of lung injury and ALI severity in young and aging lungs. Mechanistic will focus on thioredoxin interacting protein and cell death signaling to uncover molecular basis of FPL-exacerbated lung injury in the aging lungs. Finally, this study will use genetic and pharmacologic interventions in animal models to interrogate key pathologic mechanisms defining age-related exacerbation of lung inflammation. The results of this study will advance our understanding of pathologic mechanisms which determine more severe inflammation in the aging lungs and may open a new direction in controlling ALI/ARDS in the aging population by inactivating FPL-induced inflammatory cascades or preventing generation of deleterious FPL products. These findings can be used for development of protocols for advanced antioxidant and anti-inflammatory treatment of the aging population at risk.

项目摘要/摘要 衰老肺炎症的调节 老年患者的严重程度增加并延迟肺炎恢复和相关的肺损伤代表 对这个脆弱人群的严重威胁，但是这种依赖年龄的现象的分子机制 保持不当理解。随着衰老生物体中的抗氧化剂防御机制受到损害，增加 炎症过程中活性氧的产生可能会导致夸张的氧化应激。反过来， 细胞膜和循环磷脂的氧化增加导致产生 磷脂氧化（FPL）的碎片产物，可能对宿主细胞表现出有害作用。在 试点研究我们使用了质谱法，并确定了几种具有最高水平的FPL物种 发现在发炎的肺部肺部。我们的试点研究表明，FPLS的年龄依赖性升高 肺部功能障碍并损害急性肺细胞和动物模型中的血管内皮细胞（EC）屏障 受伤（ALI）。我们假设由于 氧化还原平衡失调通过直接影响肺部炎症和血管功能障碍。 内皮渗透性，FPL诱导的硫氧还蛋白相互作用蛋白的激活以及细胞死亡的激活 导致ALI恢复受损的机制。使用实时抗生素诱导的临床相关模型 - 抗性金黄色葡萄球菌（S. au，USA300 CA-MRSA临床菌株923）或热杀死S. au 概括抗生素敏感菌株的临床治疗，这项翻译研究将用于第一个 时间定量质谱法确定ALI期间衰老肺中升高的特定FPL 并测试它们在加剧肺部炎症和屏障功能障碍中的作用。 LC-MS-MS和成像MS 技术将应用于炎性肺损伤的临床前小鼠模型，以识别 在发炎的肺肺中产生的FPL，在肺样本中产生FPL分布的地图，并产生 将它们与年轻肺和衰老的肺部肺损伤和ALI严重程度相关联。机械将关注 硫氧还蛋白相互作用的蛋白质和细胞死亡信号传导，以发现FPL外科肺的分子基础 衰老肺部受伤。最后，这项研究将在动物模型中使用遗传和药理干预措施 询问定义与年龄相关的肺部炎症加剧的关键病理机制。结果 这项研究将提高我们对确定更严重的病理机制的理解 衰老肺部的炎症，并可能为控制老龄化的ALI/ARD开辟新的方向 通过失活FPL诱导的炎症级联反应或防止产生有害的FPL产品。 这些发现可用于开发用于晚期抗氧化剂和抗炎的方案 治疗处于危险中的老龄化人群。