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

超细颗粒诱导的心脏代谢毒性中巨噬细胞、脂质氧化和 Nrf2/HO-1 轴之间的相互作用

• 批准号: 10181434
• 负责人: Jesus Antonio Araujo
• 金额: $ 39.86万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-08 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10181434
• 关键词: Adipose tissue; Air Pollutants; Air Pollution; Alveolar; Alveolar Macrophages; Animals; Anti-Inflammatory Agents; Antioxidants; Aorta; Apolipoprotein E; Appearance; Arachidonic Acids; Arterial Fatty Streak; Atherosclerosis; Biological; Birth; Blood; Blood Vessels; Bone Marrow Transplantation; Bronchoalveolar Lavage Fluid; Caliber; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Chemistry; Chimera organism; Data; Deposition; Development; Diesel Exhaust; Epidemiology; Exposure to; Fatty Liver; Future; Genes; Goals; Health; Heat shock proteins; Heme Group; Hydroxyeicosatetraenoic Acids; Inflammatory; Inhalation; Inhalation Exposure; Intervention; Isoprostanes; Kinetics; Knockout Mice; Knowledge; Lead; Linoleic Acids; Lipid Peroxidation; Lipids; Lipoproteins; Lipoxygenase; Liver; Lung; Macrophage Activation; Mediating; Mediator of activation protein; Metabolic; Morbidity - disease rate; Mus; Myelogenous; Myocardial Infarction; Outcome; Oxidation-Reduction; Oxidative Stress; PF4 Gene; Particulate; Particulate Matter; Pathway interactions; Peripheral; Phase; Plasma; Play; Prevention approach; Process; Public Health; Research; Role; Signal Transduction; Stroke; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Transcriptional Activation; Transgenic Organisms; Translating; Travel; Up-Regulation; Western World; air filter; atherogenesis; cardiometabolism; cardiovascular effects; design; epidemiology study; experimental study; heme oxygenase-1; interstitial; lipid metabolism; macrophage; member; mortality; novel; novel marker; overexpression; oxidation; particle; particle exposure; preventive intervention; prophylactic; response; systemic toxicity; transcription factor; ultrafine particle; uptake

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.

项目概要/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 心血管发病率和死亡率增加这些关联主要归因于 我们发现，暴露于环境中的超细颗粒 (UFP) 会导致颗粒物 (PM) 成分的增加。 空气动力学直径小于 0.18 µm 和/或富含超细 PM 的柴油机尾气会导致脂质增加 过氧化、代谢紊乱、肝脏脂肪变性和动脉粥样硬化 吸入 PM 会产生促氧化剂。 肺部作用，但肺部作用如何转化为全身毒性的机制尚不清楚 PM 暴露还会引发肺部和全身组织（包括）的抗氧化反应。 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， 尝试抵消随之而来的有害影响。观察到的颗粒被肺泡吸收。 巨噬细胞与动脉粥样硬化斑块的发展显着相关，强烈表明这些 我们的总体假设是，细胞可能是将效应从肺部转移到全身组织的介质。 PM 暴露会促进心脏代谢毒性，首先是肺部的氧化作用，从而导致 通过激活肺泡对循环血液和全身组织产生促氧化和促炎症作用 巨噬细胞，均受骨髓抗氧化保护程度的调节，我们将通过以下方式检验这一假设。 以下三个具体目标：1）评估肺内脂质过氧化的动力学和机制 超细颗粒暴露及其与循环血液和发育中促氧化作用的关系 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中出现的动力学，例如肺、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) 确定骨髓是否受到影响。 抗氧化防御可防止 UFP 诱导的脂质过氧化、肺和心脏代谢毒性。 骨髓特异性 Nrf2 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 零背景将用于测试减少或增加的效果 3）评估肺泡巨噬细胞是否有抗氧化防御作用。 将 UFP 诱导的氧化作用从肺部转移到循环血液中。我们将开发肺泡和肺部。 巨噬细胞嵌合体的肺泡/间质巨噬细胞中具有消融的 HO-1，以剖析它们在 拟议的研究将有助于确定肺部的影响。 PM 诱导的心血管毒性的机制，以及表征有前途的新型生物标志物 健康影响，有可能有助于设计治疗和/或预防干预措施 空气污染引起的毒性。