Effects of particulate air pollution on HDL function and athersclerosis

空气颗粒物污染对 HDL 功能和动脉粥样硬化的影响

基本信息

批准号：
8892343
负责人：
Jesus Antonio Araujo
金额：
$ 15.4万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8892343
关键词：
Ablation Adipose tissue Air Air Pollutants Air Pollution Alveolar Alveolar Macrophages Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apolipoprotein E Arachidonate 5-Lipoxygenase Arachidonic Acids Area Arterial Fatty Streak Atherosclerosis Biological Assay Biological Markers Blood Vessels Breathing Caliber Cardiovascular Diseases Cardiovascular system Cells Cessation of life Chemicals Chimera organism Data Deposition Development Diesel Exhaust Disease Dose Enzymes Epidemiology Event Exhibits Exposure to Family Fatty acid glycerol esters Functional disorder Funding Future Generations Goals Health High Density Lipoproteins Hour Human Individual Inflammation Inflammatory Kinetics Knock-out Knockout Mice Lead Leukotrienes Linoleic Acids Lipid Peroxidation Lipids Lipoproteins Lipoxygenase Liver Lung Macrophage Activation Mediating Mediator of activation protein Michigan Morbidity - disease rate Mus Myocardial Infarction Nature Oxidation-Reduction Oxidative Stress Particulate Particulate Matter Pathogenesis Pathway interactions Plasma Process Property Reporter Risk Role Stroke Testing Tissues Toxic effect Translating Ultrafine Western World ambient particle design heme oxygenase-1 human subject inhibitor/antagonist macrophage migration mortality mouse model novel oxidation particle ultrafine particle uptake

项目摘要

The overall project aims to assess potential mechanisms on how exposure to air pollution leads to systemic effects consisting of increased lipid peroxidation, HDL dysfunction and enhanced atherosclerosis. Cumulative epidemiological and experimental data have shown that exposure to air pollutants leads to increased cardiovascular morbidity and mortality, especially of ischemic nature. We have found that exposures to diesel exhaust and ambient ultrafine particles (PM< 0.1 µm) lead to dysfunctional HDL characterized by reduced antioxidant and anti-inflammatory vascular protective properties. The development of dysfunctional HDL correlates with increased lipid peroxidation in systemic tissues and increased formation of atherosclerotic lesions. We have also observed that diesel exhaust leads to activation of the 5-lipoxygenase (5-LO) pathway in the liver. In the last few years, remarkable progress has been made in determining a plethora of systemic effects induced by air pollution. Many mechanistic details remain to be elucidated how air pollution leads to atherosclerosis. Our overarching hypothesis is that exposure to ambient PM results in lipid peroxidation, dysfunctional HDL and enhanced atherosclerosis via the induction of systemic prooxidant and proinflammatory effects that are mediated by the activation of macrophages and lipoxygenase pathways. We have proposed to test this hypothesis via three specific aims. During the bridging period funded by the R56 award, the effort will be focused on obtaining data to strengthen specific aims 1 and 2, as follows: 1) To evaluate whether activation of the 5-LO pathway mediates air pollution effects on lipid peroxidation, HDL dysfunction and atherosclerosis. We will explore the connections between 5-LO and Heme oxygenase-1 (HO-1) expression as well as the expression of other lipoxygenases in lungs, liver, aorta from ApoE null mice exposed to Diesel exhaust vs. filtered air. This will allow us to achieve a strong mechanistic framework between 5-LO and HO-1. 2) To assess the role of alveolar and systemic macrophages in the enhancement of lipid peroxidation, HDL dysfunction and atherosclerosis induced by air pollutants. We will expose macrophage-specific HO-1 KO mice in the ApoE null background and control littermates to diesel exhaust vs. filtered air to evaluate the impact of macrophage deletion of HO-1 on lipid peroxidation, HDL dysfunction and atherosclerotic lesions, and determine the connections between HO-1 and 5-LO. We will also develop mouse lung chimeras with ablated HO-1 and decreased antioxidant defense in their alveolar macrophages. These mice have a fluorescent reporter that will enable us to track HO-1 null alveolar macrophages and detect their migration from the lungs into systemic vessels, which will allow us to test the role of these cells in mediating systemic effects induced by diesel exhaust in future experiments.

总体项目旨在评估有关暴露于空气污染的潜在机制脂质过氧化，HDL功能障碍和增强动脉粥样硬化的影响。累积流行病学和实验数据表明，暴露于空气污染物会导致增加心血管发病率和死亡率，尤其是缺血性质。我们发现对柴油的暴露排气和环境超细颗粒（PM <0.1 µm）导致功能障碍的HDL，其特征是减少抗氧化剂和抗炎血管保护特性。功能失调的HDL的发展与全身组织中脂质过氧化的增加相关，动脉粥样硬化的形成增加病变。我们还观察到柴油排气会导致5-脂氧合酶（5-lo）途径的激活肝脏。在过去的几年中，在确定大量系统性方面取得了显着进步空气污染引起的影响。许多机械细节仍有待阐明空气污染如何导致动脉粥样硬化。我们的总体假设是，暴露于环境PM会导致脂质过氧化，功能失调的HDL和通过诱导全身性证明和促炎性的动脉粥样硬化增强巨噬细胞和脂氧合酶途径的激活介导的作用。我们已经提议通过三个特定目标检验该假设。在R56奖资助的桥接期间，这项工作将专注于获取数据以增强特定目标1和2，如下所示：1）评估是否激活 5-LO途径介导了空气污染对脂质过氧化，HDL功能障碍和动脉粥样硬化的影响。我们将探索5-LO和血红素加氧酶-1（HO-1）的连接以及暴露于柴油排气的ApoE Null小鼠中的肺，肝脏，肝主动点的其他脂氧合酶的表达。过滤空气。这将使我们能够在5-LO和HO-1之间实现强大的机械框架。 2）到评估肺泡和全身巨噬细胞在脂质过氧化增强HDL中的作用空气污染物引起的功能障碍和动脉粥样硬化。我们将暴露巨噬细胞特异性的HO-1 KO小鼠在Apoe无效的背景和控制同窝式柴油排气和过滤空气中，以评估 HO-1在脂质过氧化，HDL功能障碍和动脉粥样硬化病变上的巨噬细胞缺失，以及确定HO-1和5-LO之间的连接。我们还将开发带有消融的小鼠肺嵌合体 HO-1并改善了Alloolar巨噬细胞中的抗氧化剂防御。这些小鼠有荧光记者将使我们能够跟踪HO-1无肺泡巨噬细胞并检测其从肺部迁移进入全身血管，这将使我们能够测试这些细胞在介导由柴油机在将来的实验中排气。