Interplay Between Macrophages, Lipid Oxidation and the Nrf2/HO-1 Axis in the Cardiometabolic Toxicity Induced by Ultrafine Particles

项目总结/摘要 累积的流行病学和实验证据表明，接触空气污染物会导致 心血管疾病发病率和死亡率增加。这些协会大多被归因于 颗粒物（PM）成分。我们发现，暴露于环境超细颗粒（UFP）， 空气动力学直径小于0.18 µm，和/或柴油机尾气，富含超细PM，导致脂质增加 过氧化、代谢紊乱、肝脂肪变性和动脉粥样硬化。吸入PM会产生促氧化剂 作用于肺部，但肺部作用如何转化为全身毒性的机制是 仍然未知。PM暴露还引发肺和全身组织的抗氧化反应，包括 转录因子Nrf 2的激活及其靶基因血红素加氧酶1（HO-1）的上调， 试图抵消随之而来的有害影响。肺泡上皮细胞对颗粒物的摄取 巨噬细胞与动脉粥样硬化斑块的发展显著相关，这强烈表明， 细胞可能是将效应从肺转化到全身组织的介质。我们的首要假设是 PM暴露促进心脏代谢毒性，首先是肺部的氧化作用， 在循环血液和全身组织中通过激活肺泡 巨噬细胞，所有调节的程度骨髓抗氧化保护。我们将通过以下方式来验证这一假设： 以下三个具体目标：1）评估肺内脂质过氧化反应的动力学和机制， 超细颗粒暴露及其与循环血液中促氧化作用的关系 动脉粥样硬化我们将使用脂质过氧化副产物作为PM诱导的生物效应的跟踪信号， 并评估它们在各种组织如肺、血液、肝脏、脂肪组织和 暴露于超细颗粒与过滤空气不同时间的ApoE KO小鼠的主动脉。2)确定骨髓 抗氧化防御保护UFP诱导的脂质过氧化、肺和心脏代谢毒性。 骨髓特异性Nrf 2和HO-1 KO小鼠以及骨髓特异性HO-1转基因过表达小鼠 我们最近开发的ApoE零背景将用于测试降低或增加的影响。 抗氧化防御，分别在UFP诱导的毒性。3)评估肺泡巨噬细胞是否 将UFP诱导的氧化作用从肺部带到循环血液中。我们将发展肺泡和肺 巨噬细胞嵌合体与消融HO-1在他们的肺泡/间质巨噬细胞，以剖析他们的贡献， 将肺部的影响转移到全身血管。拟议的研究将有助于确定 机制参与PM诱导的心血管毒性，并表征有前途的新的生物标志物， 对健康的影响，有可能帮助设计治疗和/或预防干预措施， 空气污染引起的毒性。

PROJECT SUMMARY/ABSTRACT Cumulative epidemiological and experimental evidence have shown that exposure to air pollutants leads to increased cardiovascular morbidity and mortality. These associations have been mostly ascribed to the particulate matter (PM) components. We have found that exposures to ambient ultrafine particles (UFP), with an aerodynamic diameter less than 0.18 µm, and/or diesel exhaust, rich in ultrafine PM, lead to enhanced lipid peroxidation, metabolic derangements, liver steatosis and atherosclerosis. Inhalation of PM exerts prooxidant actions in the lungs but the mechanisms as to how pulmonary effects are translated into systemic toxicity are still unknown. PM exposure also triggers antioxidant responses in pulmonary and systemic tissues, including activation of transcription factor Nrf2 and upregulation of its target gene heme oxygenase 1 (HO-1), which attempt to counteract the ensuing harmful effects. The observations that particle uptake by alveolar macrophages significantly correlates with the development of atherosclerotic plaques strongly suggest that these cells are likely mediators in translating effects from the lungs to the systemic tissues. Our overarching hypothesis is that PM exposure promotes cardiometabolic toxicity starting with oxidative actions in the lungs that lead to prooxidant and proinflammatory effects in the circulating blood and systemic tissues via activation of alveolar macrophages, all modulated by the degree of myeloid anti-oxidant protection. We will test this hypothesis via the following three specific aims: 1) Assess the kinetics and mechanisms of lipid peroxidation in the lungs after ultrafine particle exposure, and their relation to prooxidant effects in the circulating blood and the development of atherosclerosis. We will use lipid peroxidation byproducts as tracking signals of PM-induced biological effects, and assess the kinetics of their appearance in various tissues such as the lungs, blood, liver, adipose tissue and aorta of ApoE KO mice exposed to ultrafine particles vs. filtered air for various times. 2) Determine if the myeloid antioxidant defense protects against UFP-induced lipid peroxidation, pulmonary and cardiometabolic toxicity. Myeloid-specific Nrf2 and HO-1 KO mice as well as myeloid-specific HO-1 Transgenic overexpresser mice in the ApoE null background, recently developed by us, will be used to test the effects of decreased or increased antioxidant defense, respectively, in the toxicity induced by UFP. 3) Evaluate whether alveolar macrophages carry UFP-induced oxidative effects from the lungs to the circulating blood. We will develop alveolar and lung macrophage chimeras with ablated HO-1 in their alveolar/interstitial macrophages to dissect their contribution in translating effects from the lungs into the systemic vessels. The proposed studies will aid in identifying mechanisms involved in PM-induced cardiovascular toxicity, and characterizing promising novel biomarkers of health effects, with the potential to aid in the design of therapeutic and/or prophylactic interventions against the toxicity induced by air pollution.