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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要发达国家的人类 80% 的时间都在室内度过，二氧化碳 (CO2) 是二氧化碳的产物。呼吸作用，呼出浓度为 40,000 ppm，导致室内二氧化碳含量高于室外。然而，三项人体实验研究使用了高度敏感的测试。认知功能（包括航空公司飞行模拟器）报告称，较高浓度的注意力会下降暴露于实际二氧化碳浓度 (<2,500 ppm) 的 2 小时内的认知功能。此外，体外和动物研究表明，相同浓度的二氧化碳会导致增强中性粒细胞（PMN）激活和伴随的脑血管渗漏可以与多种反应相互作用。我们推测，氧和氮物种（RONS）改变了它们随后与生物靶标的反应性。 CO2 吸入将 RONS 重定向到 PMN 中的一个新的生物分子子集，这导致 PMN 激活和氧化应激；这会导致脑血管渗漏，从而导致认知功能障碍。我们探索了人类在环境水平上吸入二氧化碳会导致人类认知能力下降由于 CO2 介导的亚硝化和细胞内生物分子的硝化而减少 PMN，导致细胞激活，这种新颖的高风险高回报机制模型整合。为了检验这一假设，我们对二氧化碳的认知影响进行了人体研究的实验、体外和体内数据。我们将：（1）分析 GSTM1 基因型分层志愿者中 CO2 离子认知功能的影响；以及 (2)确定CO2吸入是否导致PMN中靶蛋白的亚硝化和硝基修饰，如果这与 PMN 激活和氧化应激相关，则进行双盲、随机顺序、交叉。健康受试者 (n=24) 将以随机顺序呼吸 600 ppm（对照）和 2,500。 ppm（暴露）二氧化碳在我们的受控环境设施中持续 2 小时。将从受试者的外周血中收集 PMN 进行认知评估测试。每次暴露和测量后立即和4小时进行激活（氧化爆发，NLRP3）炎症体激活）和线粒体氧化应激。 PMN 中的细胞内蛋白将被评估为 CO2 诱导的细胞改变的潜在介质。功能；还将评估认知功能、中性粒细胞氧化应激的变化。目标蛋白的亚硝化和硝化修饰将根据 GSTM1 状态进行分层，预计影响对二氧化碳吸入的反应。积极的结果将为二氧化碳提供重要的机制数据。认知功能受损将有助于考虑室内环境中可接受的二氧化碳水平。