Impact of environmental air pollution on arginine metabolism in the lung.

环境空气污染对肺部精氨酸代谢的影响。

• 批准号: RGPIN-2018-06510
• 负责人: Scott, Jeremy
• 金额: $ 2.11万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683124
• 关键词: Impact; environmental; air; pollution; arginine

Transient epigenetic changes in gene expression can occur in response to environmental stressors. We have observed epigenetic changes of the inducible nitric oxide synthase gene (NOS2) (i.e., DNA promoter methylation) in peripheral blood monocytes over the course of 24 hours following exposures of normal healthy human subjects to fine particulate matter (PM2.5). Recent investigations from my laboratory have shown alterations in miRNA profiles that may affect gene expression of L-arginine-related metabolic pathways (i.e., those responsible for L-arginine uptake, production and catabolism of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, nitric oxide synthase and arginase), following chronic exposure of mice to diesel particulate matter from two different sources (i.e., PM2.5 collected from a diesel-fueled generator vs. a diesel forklift truck, which produce distinct PM profiles and chemical reactivities). Preliminary data in support of this proposal have shown reduced arginine bioavailability in lungs from mice exposed acutely (4hrs) to PM2.5 + ozone, as well as increased production of endogenous NOS inhibitors (methylarginines and polyamines). These changes in arginine metabolism can affect both lung function (i.e., through impaired production of the airway relaxant, nitric oxide) and cellular function (i.e., ADMA accumulation in the mitochondria can impact cellular respiration and the resultant oxidative stress). Thus, the fundamental hypothesis of this study is that exposure to PM influences the expression of proteins related to arginine metabolism, which can impact lung function and the cellular responses to PM. As a result, the goals of the current proposal are to investigate the impact of air pollution-induced alterations of L-arginine metabolism on the lung (i.e., basic lung function and responsiveness to contractile agonists) and cellular function (i.e., viability, indices of nitrosative and oxidative stress, and mitochondrial energetics). We will investigate the scope of the changes in the arginine metabolome in mice exposed acutely to coarse, fine or ultrafine PM using our unique real-time in vivo air pollution exposure unit as part of the Southern Ontario Centre for Atmospheric Aerosol Research (SOCAAR; www.socaar.utoronto.ca), and chronically using intranasal instillation of size-fractionated PM collected in the concentrated ambient particle exposure unit. We will then determine the impact of acute and chronic PM exposures on changes in the arginine metabolome in airway epithelial cells, grown at the air-liquid interface, focusing on the impact on cellular stress, mitochondrial function and the mechanisms responsible for such alterations. Findings from these investigations will provide important information with respect to the impact of exposures to environmental air pollutants on lung function.

基因表达的瞬时表观遗传变化可以在对环境压力的反应中发生。我们已经观察到诱导型一氧化氮合酶基因（NOS 2）的表观遗传变化（即，DNA启动子甲基化）在正常健康人类受试者暴露于细颗粒物（PM2.5）后24小时内外周血单核细胞中的变化。我实验室最近的研究表明，miRNA谱的改变可能影响L-精氨酸相关代谢途径的基因表达（即，负责L-精氨酸摄取、内源性一氧化氮合酶抑制剂、不对称二甲基精氨酸、一氧化氮合酶和精氨酸酶的产生和催化的那些），在小鼠慢性暴露于来自两种不同来源的柴油颗粒物质（即，从柴油发电机与柴油叉车收集的PM2.5，产生不同的PM分布和化学反应性）。支持这一提议的初步数据显示，急性暴露于PM2.5 +臭氧（4小时）的小鼠肺中精氨酸生物利用度降低，内源性NOS抑制剂（甲基精氨酸和多胺）的产生增加。精氨酸代谢的这些变化可以影响肺功能（即，通过气道松弛剂，一氧化氮的产生受损）和细胞功能（即，线粒体中的ADMA积累可影响细胞呼吸和由此产生的氧化应激）。因此，本研究的基本假设是暴露于PM影响与精氨酸代谢相关的蛋白质的表达，这可以影响肺功能和对PM的细胞反应。因此，本提案的目标是研究空气污染引起的L-精氨酸代谢改变对肺的影响（即，基本肺功能和对收缩激动剂的反应性）和细胞功能（即，活力、亚硝化和氧化应激指数以及线粒体能量学）。我们将研究急性暴露于粗颗粒、细颗粒或超细颗粒的小鼠精氨酸代谢组的变化范围，使用我们独特的实时体内空气污染暴露装置作为南安大略大气气溶胶研究中心（SOCAAR; www.socaar.utoronto.ca）的一部分，并长期使用在浓缩环境颗粒暴露装置中收集的粒度分级颗粒的鼻内滴注。然后，我们将确定急性和慢性PM暴露对气道上皮细胞中精氨酸代谢组变化的影响，生长在气液界面，重点关注对细胞应激，线粒体功能和负责这种改变的机制的影响。这些调查的结果将提供关于暴露于环境空气污染物对肺功能影响的重要信息。