Mechanisms for Cardiovascular Effects of air pollutants: Effect of Age and Sex

描述（由申请人提供）：自20世纪70年代以来，据报道，颗粒空气污染的不良健康影响出乎意料的低水平，导致科学家和公共卫生官员得出结论，长期暴露于与燃烧有关的细颗粒空气污染是心脏和肺部疾病的重要环境风险因素。尽管有许多研究调查了石油柴油（石油柴油）废气排放对呼吸系统的影响，但造成所报告的对人类健康不利影响的机制以及确定颗粒的有毒起始物种仍然难以捉摸。在美国和欧洲，从植物油或动物脂肪中提取的生物柴油正在成为未来的能源。生物柴油通常与传统柴油混合，排放测试表明，生物柴油的排放物似乎含有较低水平的碳氢化合物、一氧化碳和颗粒物（PM），但在颗粒物阶段含有较高的可溶性有机部分。年龄增长是动脉粥样硬化的一个已知危险因素，并且在心血管疾病（CVD）、自身免疫性疾病和气道过敏方面也有性别差异的报道。随着越来越多的证据表明空气污染物会加剧心血管疾病，确定动脉粥样硬化加剧的机制以及年龄和性别对吸入颗粒对潜在心血管疾病反应的影响是很重要的。要测试的假设是，与石油柴油燃烧相比，生物柴油排放的颗粒和气体在肺损伤程度和不良全身炎症反应方面存在差异。这将最终导致不同程度的动脉粥样硬化恶化，这将由动物的年龄和性别来调节。该提案将建立用于吸入研究的发动机排放物的受控生产。废气中的微粒和气体成分以及与臭氧反应后的非均相氧化产物将被表征。利用动物疾病模型，我们将确定暴露于发动机排气和特定气体和颗粒大小组分3天和9天后肺部的关键信号通路和炎症反应，量化并确定暴露于发动机排气后诱导的细胞类型（例如树突状细胞，肺泡巨噬细胞，CD4+ T细胞）。并确定长期暴露于废气中对小鼠动脉粥样硬化发展的影响，特别关注动物年龄和性别的调节。这些方法将有助于深入了解弱势群体（妇女和老年人）的易感性以及干预和治疗方法。

DESCRIPTION (provided by applicant): Since the 1970's, adverse health effects have been reported at unexpectedly low levels of particulate air pollution, leading scientists and public health officials to conclude that long-term exposure to combustion-related fine particulate air pollution is a significant environmental risk factor for heart and lung diseases. Despite numerous studies examining the effects of petroleum diesel (petrodiesel) exhaust emissions on the respiratory system, the mechanisms responsible for the reported adverse human health effects and pinpointing the particulate's toxic initiating species remain elusive. Biodiesel fuel made from vegetable oil or animal fat is gaining momentum as the energy source of the future both in the U.S. and Europe. Biodiesel is typically blended into conventional diesel fuel, and emission testing has shown that biodiesel emissions appear to contain reduced levels of hydrocarbons, carbon monoxide and particulate matter (PM) but a higher soluble organic fraction in the particulate phase. Advancing age is a known risk factor for atherosclerosis, and sex differences in cardiovascular disease (CVD), autoimmune disease and airway hypersensitivity have been reported. With increased evidence that air pollutants act to exacerbate CVD, it is important to determine the mechanisms responsible for the exacerbation of atherosclerosis and the influence of age and sex on the responses to inhaled particles on underlying CVD. The hypothesis to be tested is that particulate and gaseous emissions from biodiesel compared to petrodiesel combustion will differ in the extent of lung injury and adverse systemic inflammatory responses. This will lead ultimately to different degrees of exacerbation of atherosclerosis, which will be modulated by the age and sex of the animal. This proposal will establish controlled production of engine emissions to be used in inhalation studies. The particulate and gaseous components of the exhaust as well as the heterogeneous oxidation products upon reaction with ozone will be characterized. Using animal models of disease, we will identify key signaling pathways and inflammatory responses in the lung after 3- and 9-day exposures to engine exhaust and specific gaseous and particulate size fractions, quantify and determine the types of cells (e.g. dendritic cells, alveolar macrophages, CD4+ T cells) induced after exposures to engine exhaust, and determine the effects of chronic exposure to exhaust on the development of atherosclerosis in mice with a specific focus on modulation by the age and sex of the animals. These approaches will provide insight into susceptibility of vulnerable populations (women and the elderly) and approaches for intervention and therapy. PUBLIC HEALTH RELEVANCE: Biodiesel has been touted as an important strategy for energy independence as well as sustainability in terms of agricultural production and reduced environmental impact from the transportation sector, but as with petrodiesel, combustion of biodiesel produces particulate air pollution. Adverse health effects of airborne particulate matter (PM) have been reported at unexpectedly low concentrations, leading scientists and public health officials to conclude that long-term exposure to combustion-related particulate air pollution is a significant environmental risk factor for heart and lung diseases. Despite the belief that biofuels may be better for the environment and for human health, there is very limited information about the biological effects of biodiesel emissions so this proposal will compare and contrast the biological effects of emission particles from the combustion of petro- and biodiesel and the influence of age and gender on these responses in an effort to lay the groundwork for future studies aimed at elucidating the mechanisms responsible for the significant relationship between airborne PM and lung and heart disease and at developing approaches to reduce the adverse health consequences of air pollution.