Acute Cognitive Impairments Following Exposure to Inhaled CO2: Translating Mouse Mechanisms to Humans

吸入二氧化碳后的急性认知障碍：将小鼠机制转化为人类

• 批准号: 10688101
• 负责人: HOWARD M KIPEN
• 金额: $ 19.63万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-23 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688101
• 关键词: Acute; Air; Animals; Biochemical; Biological; Blood; Blood Vessels; Brain; Breathing; Carbon Dioxide; Cell physiology; Cells; Cognitive; Communities; Controlled Environment; Cross-Over Studies; Data; Decision Making; Developed Countries; Diffusion; Double-Blind Method; Exposure to; Extravasation; Flying body movement; GSTM1 gene; Gases; Genotype; Glutathione; Health; Home; Hour; Human; Human Volunteers; Impaired cognition; In Vitro; Indoor Air Pollution; Indoor environment; Inflammasome; Inflammation; Inflammatory; Inhalation; Ions; Lipids; Measurement; Measures; Mediating; Mediator; Mitochondria; Modeling; Modification; Mus; Nitrogen; Nitrosation; Nucleic Acids; Oxidative Stress; Oxygen; Performance; Peroxonitrite; Persons; Physiological; Positioning Attribute; Productivity; Proteins; Public Health; Randomized; Reaction; Reporting; Respiration; Respiratory Burst; Rodent; Safety; Schools; Site-Directed Mutagenesis; Sulfhydryl Compounds; Symptoms; Testing; Time; Translating; Tyrosine; Volatilization; cognitive function; cognitive performance; cognitive system; cognitive testing; cytokine; experimental study; exposed human population; healthy volunteer; high reward; high risk; human data; in vivo; individual response; indoor concentrations; innovation; neutrophil; nitration; novel; oxidation; particle; peripheral blood; pollutant; simulation; volunteer

Project Summary/Abstract Humans in developed countries spend 80% of their time indoors. Carbon dioxide (CO2) is a product of respiration, expired at a concentration of 40,000 ppm, leading to higher levels indoors than outdoors. CO2 is widely regarded as nontoxic. However, three human experimental studies using highly sensitive tests of cognitive function including an airline flight simulator, reported concentration-related decrements in higher cognitive function during 2 hr. exposures to elevated, but real-world CO2 concentrations (<2,500 ppm). Additionally, in vitro and animal studies demonstrated that CO2 at the same concentrations caused enhanced neutrophil (PMN) activation and accompanying brain vascular leak. CO2 can interact with a variety of reactive oxygen and nitrogen species (RONS), altering their subsequent reactivity with biological targets. We speculate that CO2 inhalation redirects RONS towards a novel subset of biomolecules in PMN and that this leads to PMN activation and oxidative stress; this causes brain vascular leak, and consequently cognitive dysfunction. We hypothesize that exposure of humans to inhaled CO2 at environmental levels will lead to human cognitive decrements as a consequence of CO2-mediated nitrosation and nitration of intracellular biomolecules in PMN, leading to cellular activation. This novel high-risk high-reward mechanistic model integrates experimental, in vitro, and in vivo data with human studies on cognitive effects of CO2. To test this hypothesis, we will: (1) analyze the effects of CO2 ion cognitive function in volunteers stratified on GSTM1 genotype; and (2) determine whether CO2 inhalation results in nitrosative and nitrative modification of target proteins in PMN, and if this is correlated with PMN activation and oxidative stress. A double-blind, randomized order, cross-over study will be performed. Healthy subjects (n=24) will breathe in random order 600 ppm (control), and 2,500 ppm (exposed) CO2 for 2 hrs. in our controlled environmental facility. The Strategic Management Systems cognitive assessment test will be administered. PMNs will be collected from subjects’ peripheral blood immediately and 4 hr. after each exposure and measurements made of activation (oxidative burst, NLRP3 inflammasome activation) and mitochondrial oxidative stress. Oxidation, nitrosation, and nitration of intracellular proteins in PMN will be assessed as potential mediators of CO2 induced alterations in cellular function; release of microparticles will also be assessed. Changes in cognitive function, PMN oxidative stress and nitrosative and nitrative modification of target proteins will be stratified on GSTM1 status, predicted to influence responsiveness to CO2 inhalation. Positive results will provide important mechanistic data on CO2 and impaired cognitive function that will inform consideration of acceptable CO2 levels in indoor environments.

项目摘要/摘要 发达国家的人类将其80％的时间在室内花费。二氧化碳（CO2）是 呼吸以40,000 ppm的浓度到期，导致室内水平高于室外。二氧化碳是 被广泛认为是无毒的。但是，三项人类实验研究，使用高度敏感的测试 认知功能，包括航空公司飞行模拟器，报告较高的浓度相关的降低 2小时内的认知功能。暴露于升高但现实世界中的二氧化碳浓度（<2,500 ppm）。 此外，体外和动物研究表明，相同浓度的二氧化碳引起了增强 中性粒细胞（PMN）激活并进行脑血管泄漏。 CO2可以与各种反应性相互作用 氧和氮种（RON），改变了它们随后与生物学靶标的反应性。我们推测 该二氧化碳吸入将Rons重定向到PMN中的新型生物分子子集，这导致 PMN激活和氧化应激；这会导致脑血管泄漏，从而导致认知功能障碍。 我们假设人类暴露于环境水平上的二氧化碳将导致人类认知 由于二氧化碳介导的硝化和细胞内生物分子硝化而减少 PMN，导致细胞激活。这个新颖的高风险高回报机械模型集成了 实验性，体外和体内数据与人类对CO2认知作用的研究。为了检验这一假设， 我们将：（1）分析在GSTM1基因型上分层的志愿者中CO2离子认知功能的影响；和 （2）确定二氧化碳吸入是否会导致PMN中靶蛋白的亚硝化和硝化修饰， 如果这与PMN激活和氧化应激相关。双盲，随机秩序，交叉 研究将进行。健康受试者（n = 24）将以随机顺序600 ppm（对照）和2,500 PPM（暴露）CO2 2小时。在我们受控的环境设施中。战略管理系统 认知评估测试将进行。 PMN将从受试者的外周血中收集 立即和4小时。在每次暴露和激活制成的测量之后（氧化爆发，NLRP3） 炎症体激活）和线粒体氧化应激。氧化，硝化和硝化 PMN中的细胞内蛋白将被评估为二氧化碳诱导的潜在介体在细胞中的改变 功能;还将评估微粒的释放。认知功能的变化，PMN氧化应激 靶蛋白的亚硝化剂和硝化修饰将根据GSTM1状态进行分层，预测为 影响对二氧化碳吸入的反应。积极的结果将为CO2提供重要的机械数据 认知功能受损，可以考虑在室内环境中考虑可接受的二氧化碳水平。