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.

项目摘要/摘要 累积流行病学和实验证据表明，暴露于空气污染物会导致 心血管发病率和死亡率增加。这些关联主要归因于 颗粒物（PM）组件。我们发现，对环境超细颗粒（UFP）的接触， 空气动力学直径小于0.18 µm和/或柴油排气，富含Ultrafine PM，导致脂质增强 过氧化，代谢进化，肝脏脂肪变性和动脉粥样硬化。吸入PM施加证明 肺部的作用，但是关于如何将肺作用转化为全身毒性的机制是 仍然未知。 PM暴露还触发肺和全身组织中的抗氧化剂反应，包括 转录因子NRF2的激活及其靶基因血红素氧酶1（HO-1）的上调， 试图抵消随之而来的有害影响。牙槽吸收粒子吸收的观察结果 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 细胞可能是将肺部转化为全身组织的介体。我们的总体假设 是，PM暴露会促进心脏代谢毒性，从肺部的氧化作用开始 通过激活肺泡，在循环血液和全身组织中的促炎和促炎作用 巨噬细胞，全部由髓样抗氧化剂保护程度调节。我们将通过 以下三个具体目的：1）评估肺中脂质过氧化的动力学和机制 超铁颗粒的暴露及其与循环血液中的毒性影响的关系和发育 动脉粥样硬化。我们将使用脂质过氧化副产品作为跟踪PM诱导的生物学效应的信号， 并评估它们在各种时机中出现的动力学，例如肺，血液，肝脏，脂肪组织和 APOE KO小鼠的主动脉暴露于超细颗粒与过滤空气的不同时间。 2）确定是否髓样 抗氧化剂防御可预防UFP诱导的脂质过氧化，肺和心脏代谢毒性。 在 我们最近开发的Apoe Null背景将用于测试减少或增加的影响 UFP诱导的毒性中分别是抗氧化剂防御。 3）评估是否肺泡巨噬细胞 从肺到循环的血液中携带UFP诱导的氧化作用。我们将发展肺泡和肺 巨噬细胞嵌合在其肺泡/间质巨噬细胞中带有烧蚀的HO-1，以剖析其在 将肺部的影响转化为全身vissels。拟议的研究将有助于确定 参与PM诱导的心血管毒性的机制，并表征有希望的新型生物标志物 健康影响，有可能帮助设计理论和/或预防性干预措施 空气污染引起的毒性。