Dissecting the Role of Arachidonic Acid Metabolic Pathways Involved in Resolution Versus Progression of PM-Induced Cardiometabolic Toxicity

剖析花生四烯酸代谢途径在 PM 诱导的心脏代谢毒性的消退与进展中的作用

• 批准号: 10350448
• 负责人: Jesus Antonio Araujo
• 金额: $ 54.35万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-11 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350448
• 关键词: Air Pollution; Alveolar; Animals; Anti-Inflammatory Agents; Antioxidants; Aorta; Apolipoprotein E; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Atherosclerosis; Birth; Blood; Blood Vessels; Bronchoalveolar Lavage Fluid; Caliber; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic; Critical Pathways; Data; Development; Diesel Exhaust; Disease; Down-Regulation; Enzymes; Epidemiology; Exposure to; Fatty Liver; Goals; Hepatic; Hepatitis; Hydroxyeicosatetraenoic Acids; Infiltration; Inflammation; Inflammatory; Inhalation; Inhalation Exposure; Isoprostanes; Knockout Mice; Knowledge; Lead; Leukotriene B4; Linoleic Acids; Lipid Peroxidation; Lipids; Lipoproteins; Lipoxins; Liver; Low-Density Lipoproteins; Lung; Mediating; Metabolic; Metabolic Pathway; Metabolism; Molecular; Morbidity - disease rate; Mus; Organ; Outcome; Oxidative Stress; Particulate; Particulate Matter; Pathway interactions; Pharmacology; Phase; Plasma; Protocols documentation; Reporting; Research; Resolution; Role; Steatohepatitis; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Triglycerides; Ultrafine; Work; ambient particle; cardiometabolism; design; epidemiology study; fatty liver disease; fine particles; inhibitor; lipid metabolism; mRNA Expression; macrophage; mortality; particle; particle exposure; preventive intervention; prophylactic; protein expression; rational design; response; ultrafine particle; volatile organic compound

ABSTRACT Epidemiological and experimental data have shown that chronic exposure to ambient particulate matter (PM) leads to exacerbation of atherosclerosis, and increased cardiovascular morbidity and mortality. We have shown that mouse exposures to diesel exhaust and ultrafine particles (PM< 0.18 µm) lead to increased lipid peroxidation in the lungs and systemic tissues, accompanied by effects on plasma lipoproteins, disturbances in lipid metabolism, liver steatosis, and atherosclerosis, all components of the so-called cardiometabolic syndrome. PM- induction of these disorders is thought to involve chronic and persistent activation of inflammatory pathways. However, while chronic exposure to PM < 2.5 µm (PM2.5) has been reported to result in steatohepatitis, we have shown that chronic exposure to diesel exhaust also leads to triglyceride accumulation in the liver (steatosis) but without the inflammatory component, suggesting that PM with different compositions could have different abilities to activate inflammatory pathways after chronic exposures. This project has been designed to dissect molecular pathways involved in the development and progression versus inhibition or resolution of inflammation. Our central hypothesis is that PM exposure promotes cardiometabolic toxicity via prooxidant and proinflammatory effects that lead to wide dysregulation of arachidonic acid metabolic pathways, with activation of 5-lipoxygenase, overpowering the counteracting actions of homeostatic protective responses when that activation is persistent. We will test this hypothesis via three specific aims: 1) Determine molecular pathways involved in the inhibition of steatohepatitis after exposure to diesel exhaust. 2) Dissect molecular pathways and toxic constituents involved in the development and progression of steatohepatitis and atherosclerosis after exposure to ultrafine particles. 3) Determine whether PM-induced chronic inflammation is mediated by the persistent activation of the 5-lipoxygenase (5-LO) pathway, and explore the therapeutic potential of blocking this pathway to mitigate the cardiometabolic toxicity and resolve inflammation induced by PM. In aims 1 and 2, LDL-R KO mice will be exposed to whole diesel exhaust or ultrafine concentrated ambient particles, respectively, to evaluate the effect of different PMs on the development of fatty liver disease and atherosclerosis in experimental protocols of continuous or intermittent exposures to PM. Intervening molecular pathways will be analyzed in various tissues (lungs, blood, liver, aorta), especially those involving arachidonic acid metabolism and antioxidant homeostatic responses. Data will be integrated with inflammatory endpoints obtained in various tissues, alveolar and systemic macrophages. Comparison among contrasting effects observed in both aims will enable identification of critical pathways responsible for development versus resolution of chronic inflammation. In aim 3, LDL-R KO mice deficient in 5-LO or treated with pharmacological inhibitors of the 5-LO pathway will be tested to evaluate the role of 5-LO activation in mediating PM-induced inflammation. This project will help in better understanding of PM-induced toxicity with prophylactic or therapeutic implications.

抽象的 流行病学和实验数据表明，长期暴露于环境颗粒物 (PM) 导致动脉粥样硬化加剧，心血管疾病发病率和死亡率增加。我们已经展示了 小鼠暴露于柴油机尾气和超细颗粒 (PM< 0.18 µm) 会导致脂质过氧化增加 在肺部和全身组织中，伴随着对血浆脂蛋白的影响，脂质的紊乱 新陈代谢、肝脏脂肪变性和动脉粥样硬化，这些都是所谓的心脏代谢综合征的组成部分。下午- 人们认为这些疾病的诱发涉及炎症途径的慢性和持续激活。 然而，虽然据报道长期接触 PM < 2.5 µm (PM2.5) 会导致脂肪性肝炎，但我们有 研究表明，长期接触柴油机尾气也会导致甘油三酯在肝脏中积聚（脂肪变性），但 没有炎症成分，表明不同成分的 PM 可能具有不同的能力 长期暴露后激活炎症途径。该项目旨在剖析分子 涉及炎症发生和进展与抑制或消退的途径。我们的 中心假设是 PM 暴露通过促氧化和促炎症促进心脏代谢毒性 导致花生四烯酸代谢途径广泛失调的影响，并激活 5-脂氧合酶， 当这种激活持续存在时，会压倒稳态保护反应的抵消作用。 我们将通过三个具体目标来检验这一假设：1）确定参与抑制的分子途径 接触柴油机尾气后发生脂肪性肝炎。 2) 剖析分子途径和有毒成分 参与接触超细颗粒后脂肪性肝炎和动脉粥样硬化的发生和进展 颗粒。 3) 确定 PM 诱导的慢性炎症是否是由持续激活的 5-脂氧合酶 (5-LO) 途径，并探索阻断该途径以减轻 心脏代谢毒性并解决 PM 引起的炎症。在目标 1 和 2 中，LDL-R KO 小鼠将 分别暴露于全部柴油机尾气或超细浓缩环境颗粒中，以评估效果 实验方案中不同 PM 对脂肪肝疾病和动脉粥样硬化发展的影响 连续或间歇性接触 PM。将分析各种组织中的干预分子途径 （肺、血液、肝脏、主动脉），特别是那些涉及花生四烯酸代谢和抗氧化稳态的 回应。数据将与在各种组织、肺泡和全身获得的炎症终点相结合 巨噬细胞。比较两个目标中观察到的对比效果将能够识别关键的 负责慢性炎症的发展与消退的途径。在目标 3 中，LDL-R KO 小鼠 缺乏 5-LO 或接受 5-LO 途径药物抑制剂治疗的患者将接受测试以评估 5-LO 激活在介导 PM 诱导的炎症中的作用。该项目将有助于更好地了解 PM 引起的毒性具有预防或治疗意义。