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.

项目总结/摘要 衰老肺的炎症调节 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了 对这个脆弱的群体来说是一个严重的威胁，但是这种年龄依赖现象的分子机制 人们对它了解仍然很少。随着衰老机体的抗氧化防御机制受损， 在炎症过程中活性氧物质的产生可引起过度的氧化应激。反过来， 细胞膜和循环磷脂的氧化增加导致产生一个家族的磷脂酶， 磷脂氧化（FPL）的片段化产物，其可能对宿主细胞表现出有害作用。在 我们使用质谱法进行了初步研究，并确定了几种水平最高的FPL物质 在发炎老化的肺里找到的我们的初步研究表明，年龄依赖性的FPL升高增加了 在急性肺损伤的细胞和动物模型中， 损伤（ALI）。我们假设，在老龄化人口中FPL的产生增加是由于 氧化还原平衡失调通过直接作用于 内皮通透性、FPL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。使用临床相关的由活抗生素诱导的ALI模型- 耐药金黄色葡萄球菌（S. Au、USA 300 CA-MRSA临床菌株923）或热灭活的S. Au 概括抗生素敏感菌株的临床治疗，这项转化研究将首次采用 时间定量质谱法鉴定ALI期间老化肺中升高的特定FPL 并测试它们在肺部炎症和屏障功能障碍恶化中的作用。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 在发炎的老化肺中产生的FPL，生成肺样品中FPL分布的图， 将它们与年轻和老年肺的肺损伤和ALI严重程度的地形图联系起来。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，以揭示FPL加重肺的分子基础 老化的肺部损伤。最后，本研究将在动物模型中使用遗传和药理学干预 探讨与年龄相关的肺部炎症加重的关键病理机制。结果 这项研究的结果将促进我们对病理机制的理解， 这可能为控制老年人群中的ALI/ARDS开辟了新的方向 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高级抗氧化剂和抗炎剂的方案 治疗处于危险中的老年人。