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

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/文摘