权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

整个项目旨在评估暴露于空气污染如何导致系统性疾病的潜在机制