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.

摘要 流行病学和实验数据表明，长期接触周围环境颗粒物(PM) 导致动脉粥样硬化加重，增加心血管发病率和死亡率。我们已经展示了 小鼠暴露于柴油废气和超细颗粒物(PM&lt；0.18微米)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，脂质紊乱 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1：00- 这些疾病的诱导被认为涉及慢性和持续性的炎症途径的激活。 然而，尽管有报道称长期接触PM&lt；2.5微米(PM2.5)会导致脂肪性肝炎，但我们已经 研究表明，长期暴露在柴油废气中也会导致甘油三酯在肝脏中积聚(脂肪变性)，但 没有炎性成分，提示不同成分的PM可能有不同的能力 在慢性暴露后激活炎症途径。这个项目被设计成对分子进行解剖 参与发展和进展的途径，而不是抑制或消除炎症。我们的 中心假设是PM暴露通过促氧化剂和促炎性物质促进心脏代谢毒性 导致花生四烯酸代谢途径广泛失调的效应，激活5-脂氧合酶， 当这种激活持续时，压倒动态平衡保护性反应的抵消作用。 我们将通过三个具体目标来验证这一假说：1)确定参与抑制的分子途径 暴露在柴油废气中的脂肪性肝炎。2)剖析分子途径和毒性成分 参与接触超细粉后脂肪性肝炎和动脉粥样硬化的发生发展 粒子。3)确定PM诱导的慢性炎症是否是通过持续激活 5-脂氧合酶(5-LO)途径，并探讨阻断这一途径以减轻 PM的心脏代谢毒性和消炎作用在AIMS 1和2中，低密度脂蛋白受体KO小鼠将 分别暴露在全柴油尾气或超细浓度环境颗粒物中，以评估效果 不同PM对脂肪肝和动脉粥样硬化发生发展的影响 连续或间歇性接触PM将在不同的组织中分析介入的分子途径 (肺、血、肝、动脉)，尤其是涉及花生四烯酸代谢和抗氧化剂稳态的那些 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。在两个目标中观察到的对比效果之间的比较将能够识别关键 负责发展的途径与慢性炎症的解决途径。在AIM 3中，低密度脂蛋白受体KO小鼠 5-LO缺乏或用5-LO途径的药物抑制剂治疗的人将接受测试，以评估 5-LO激活在PM诱导的炎症反应中的作用这个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。