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: 10402876
• 负责人: Jesus Antonio Araujo
• 金额: $ 39.74万
• 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/10402876
• 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; rational design; 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.

项目总结/文摘