Modulation of inflammation in aging lung

调节衰老肺部的炎症

• 批准号: 10329996
• 负责人: Konstantin Birukov
• 金额: $ 38.43万
• 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/10329996
• 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; 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; Pulmonary Inflammation; 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.

项目摘要/摘要 肺老化过程中炎症的调节作用 老年患者肺炎和相关肺损伤的严重程度增加和恢复延迟代表 对这一脆弱群体的严重威胁，但这种依赖年龄的现象的分子机制 人们对此仍然知之甚少。随着衰老生物体的抗氧化防御机制受损，增加 炎症过程中产生的活性氧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)的碎裂产物，可能对宿主细胞产生有害影响。在……里面 初步研究我们使用了质谱学方法，鉴定出了几种含量最高的fpl物种。 在发炎的老化肺部中发现。我们的初步研究表明，随着年龄的增加，FFL的增加 急性肺细胞和动物模型肺功能障碍及血管内皮细胞屏障受损 损伤(ALI)。我们假设在老龄化人口中增加的FPL的产生是由于 氧化还原平衡失调通过直接影响肺组织炎症和血管功能障碍 内皮通透性、甘油三酯诱导的硫氧还蛋白相互作用蛋白的激活和细胞死亡的激活 导致ALI恢复受损的机制。使用活体抗生素诱导的临床相关ALI模型- 耐药金黄色葡萄球菌(金黄色葡萄球菌，USA300 CA-MRSA临床菌株923)或热致死金黄色葡萄球菌 总结抗生素敏感菌株的临床治疗，这项转化研究将首次采用 定量质谱法鉴定ALI时老化肺组织中特异的FPL升高 并测试它们在加重肺部炎症和屏障功能障碍中的作用。LC-MS-MS和成像质谱仪 这些技术将应用于临床前炎性肺损伤的小鼠模型，以确定 在炎症老化的肺中产生的fpl，生成fpl在肺样本中的分布图和 将它们与年轻和老年肺损伤的地形图和ALI严重程度联系起来。机械师将专注于 硫氧还蛋白相互作用蛋白和细胞死亡信号揭示FPL加重肺的分子基础 肺部老化的损伤。最后，这项研究将在动物模型中使用遗传和药物干预。 探讨与年龄相关的肺部炎症加重的关键病理机制。结果是 这项研究将促进我们对病理机制的理解，这些机制决定了 老年肺部炎症，可能为控制老龄人口ALI/ARDS开辟新的方向 通过灭活FPL诱导的炎性级联反应或防止有害的FPL产品的产生。 这些发现可用于开发高级抗氧化剂和抗炎药物的方案 对高危老龄人口的治理。