Modulation of inflammation in aging lung

调节衰老肺部的炎症

• 批准号: 10112958
• 负责人: Konstantin Birukov
• 金额: $ 38.36万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112958
• 关键词: Acute Lung Injury; Adult; Adult Respiratory Distress Syndrome; 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 Inflammation; Lung diseases; Lung infections; Maps; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Mus; Older Population; Organ; Organism; Oxidation-Reduction; Oxidative Stress; Oxides; Pathogenicity; Pathologic; Pathway interactions; Permeability; Pharmacology; Phospholipids; Pilot Projects; Pneumonia; Populations at Risk; Predisposition; Process; Production; Property; Reaction; Reactive Oxygen Species; Recovery; 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; base; clinically relevant; injury recovery; lung injury; macrophage; methicillin resistant Staphylococcus aureus; mouse model; neutrophil; novel therapeutics; older patient; oxidant stress; oxidation; particle; pathogenic bacteria; pre-clinical; prevent; protein activation; 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.

项目概要/摘要 调节衰老肺部的炎症 老年患者肺炎和相关肺损伤的严重程度增加和恢复延迟 对这一弱势群体构成严重威胁，但这种年龄依赖性现象的分子机制 仍然知之甚少。随着衰老有机体的抗氧化防御机制受损， 炎症期间活性氧的产生可能会导致过度的氧化应激。反过来， 细胞膜和循环磷脂的氧化增加导致一系列 磷脂氧化（FPL）的碎片产物，可能对宿主细胞产生有害影响。在 我们使用质谱方法进行试点研究，并确定了几种含量最高的 FPL 物种 发现于发炎老化的肺部。我们的初步研究表明，FPL 的年龄依赖性升高会增强 在急性肺细胞和动物模型中导致肺功能障碍并损害血管内皮细胞（EC）屏障 损伤（ALI）。我们假设老龄化人口中 FPL 的产生增加是由于 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 内皮通透性、FPL 诱导的硫氧还蛋白相互作用蛋白激活以及细胞死亡激活 导致 ALI 恢复受损的机制。使用活抗生素诱导的 ALI 临床相关模型 耐药金黄色葡萄球菌（S. au，USA300 CA-MRSA 临床菌株 923）或热灭活的 S. au 这项转化研究将首次采用抗生素敏感菌株的临床治疗方法 时间定量质谱方法来识别 ALI 期间老化肺部中升高的特定 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 技术将应用于炎症性肺损伤的临床前小鼠模型，以确定 发炎老化肺部产生的 FPL，生成肺部样本中 FPL 分布图，并 将它们与年轻和衰老肺部的肺损伤地形和 ALI 严重程度联系起来。机制将重点 硫氧还蛋白相互作用蛋白和细胞死亡信号传导揭示 FPL 加重肺的分子基础 老化肺部受伤。最后，这项研究将在动物模型中使用遗传和药理学干预措施 探究定义与年龄相关的肺部炎症恶化的关键病理机制。结果 这项研究将增进我们对病理机制的理解，这些机制决定了更严重的 衰老肺部的炎症，可能为控制老年人群中的 ALI/ARDS 开辟新方向 通过灭活 FPL 诱导的炎症级联反应或防止有害 FPL 产物的产生。 这些发现可用于开发先进的抗氧化和抗炎方案 治疗面临风险的老龄化人口。