Effects of particulate air pollution on HDL function and athersclerosis

整个项目旨在评估暴露在空气污染中如何导致系统性疾病的潜在机制。 影响包括增加脂质过氧化，高密度脂蛋白功能障碍和加强动脉粥样硬化。累计 流行病学和实验数据表明，暴露在空气污染物中会导致 心血管疾病的发病率和死亡率，尤其是缺血性心脏病。我们发现接触柴油会导致 废气和周围的超细颗粒物(PM&lt；0.1µm)会导致高密度脂蛋白功能障碍，其特征是 具有抗氧化和抗炎的血管保护作用。高密度脂蛋白功能障碍的研究进展 与全身组织中脂质过氧化增加和动脉粥样硬化形成增加有关 损伤。我们还观察到柴油尾气导致5-脂氧合酶(5-LO)途径的激活。 肝脏。在过去的几年里，在确定过多的系统性疾病方面取得了显著进展。 空气污染造成的影响。许多机制细节仍有待阐明空气污染是如何导致 动脉硬化。我们的主要假设是暴露在环境PM中会导致脂质过氧化， 全身性促氧化剂和促炎性物质诱导的高密度脂蛋白紊乱和动脉粥样硬化增强 巨噬细胞激活和脂氧合酶途径介导的效应。我们已经提议 通过三个具体目标来检验这一假设。在由R56奖励资助的过渡期内，努力将 专注于获取数据以加强具体目标1和2，具体如下：1)评估是否激活 5-LO途径参与了空气污染对脂质过氧化、高密度脂蛋白紊乱和动脉粥样硬化的影响。 我们将探讨5-LO和血红素加氧酶-1(HO-1)表达之间的关系，以及5-LO与HO-1表达的关系。 柴油尾气暴露对ApoE基因缺失小鼠肺、肝、主动脉中其他脂氧合酶表达的影响 过滤后的空气。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)至 评估肺泡巨噬细胞和系统巨噬细胞在增强脂质过氧化中的作用 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为零的背景和对照垃圾中评估柴油废气与过滤空气的影响 巨噬细胞缺失HO-1对脂质过氧化、高密度脂蛋白功能障碍和动脉粥样硬化损害的影响 确定HO-1和5-LO之间的连接。我们还将开发具有消融作用的小鼠肺嵌合体 HO-1和降低其肺泡巨噬细胞的抗氧化防御。这些老鼠身上有一种荧光 这将使我们能够追踪HO-1缺失的肺泡巨噬细胞，并检测它们从肺部的迁移 进入全身血管，这将使我们能够测试这些细胞在介导由 柴油尾气在未来的实验中。

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.