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

项目摘要/摘要 累积的流行病学和实验证据表明，暴露在空气污染物中会导致 心血管发病率和死亡率增加。这些联系大多被归因于 颗粒物(PM)成分。我们发现，暴露在环境超细颗粒物(UFP)中，具有 空气动力学直径小于0.18微米和/或柴油机排气，富含超细颗粒物，导致血脂升高 过氧化、代谢紊乱、肝脏脂肪变性和动脉粥样硬化。吸入颗粒物会产生促氧化剂 但肺效应如何转化为全身毒性的机制是 仍然未知。PM暴露还会触发肺和全身组织的抗氧化反应，包括 转录因子Nrf2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。肺泡对颗粒物摄取的观察 巨噬细胞与动脉粥样硬化斑块的发展显著相关强烈提示这些 细胞很可能是将效应从肺部传递到全身组织的媒介。我们最重要的假设 PM暴露会促进心脏代谢毒性，首先是肺部的氧化作用，导致 肺泡激活在循环血液和全身组织中的促氧化和促炎作用 巨噬细胞，都受到髓系抗氧化保护程度的调节。我们将通过以下方式验证这一假设 以下三个具体目标：1)评估肺组织脂质过氧化的动力学和机制 超细颗粒物暴露及其与循环血液中促氧化作用和发育的关系 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， 并评估它们在不同组织中的出现动力学，如肺、血、肝、脂肪组织和 ApoE KO小鼠不同时间暴露于超细颗粒物与过滤空气的比较。2)确定髓系细胞是否 抗氧化剂防御UFP诱导的脂质过氧化、肺和心脏代谢毒性。 髓系特异性Nrf2和HO-1 KO小鼠以及髓系特异性HO-1转基因高表达小鼠 我们最近开发的ApoE零背景将被用来测试减少或增加的影响 在UFP诱导的毒性中分别具有抗氧化防御作用。3)评估肺泡巨噬细胞 将UFP诱导的氧化效应从肺部传递到循环血液。我们将发展肺泡和肺 肺泡/间质巨噬细胞中含有HO-1的巨噬细胞嵌合体的研究 将肺部的影响转化为全身血管。拟议的研究将有助于确定 PM引起心血管毒性的机制，以及有前景的新生物标志物的特征 对健康的影响，有可能帮助设计治疗和/或预防措施，防止 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.