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，长期暴露于环境特定物质（PM） 导致动脉粥样硬化加剧，并增加心血管发病率和死亡率。我们已经显示了 小鼠暴露于柴油排气和超细颗粒（PM <0.18 µm）导致脂质过氧化增加 在肺部和全身组织中，通过对血浆脂蛋白的影响而完成的脂质灾难 代谢，肝脏脂肪变性和动脉粥样硬化，这是所谓的心脏代谢综合征的所有成分。下午- 这些疾病的诱导被认为涉及炎症途径的慢性和持续激活。 但是，虽然据报道长期暴露于PM <2.5 µm（PM2.5）会导致脂肪性肝炎，但我们已经 表明长期暴露于柴油排气的还会导致肝脏中甘油三酸酯的积累（脂肪变性），但 没有炎症成分，表明具有不同组成的PM可能具有不同的能力 慢性暴露后激活炎症途径。该项目旨在剖析分子 参与发育与进展与抑制或炎症的抑制途径。我们的 中心假设是，PM暴露通过证明和促炎性促进心脏代谢毒性 导致蛛网膜酸代谢途径的广泛失调，并激活5-脂氧合酶， 当激活持续进行时，要压倒稳态保护反应的抵消动作。 我们将通过三个特定目的检验这一假设：1）确定与抑制有关的分子途径 暴露于柴油排气后的脂肪性肝炎。 2）剖析分子途径和有毒构成 暴露于Ultrafine后，参与脂肪性肝炎和动脉粥样硬化的发展和进展 颗粒。 3）确定PM诱导的慢性炎症是否通过持续激活介导 5-脂氧合酶（5-LO）途径，并探索阻止这种减轻该途径的治疗潜力 心脏代谢毒性并解决PM诱导的注射。在AIMS 1和2中，LDL-R KO小鼠将是 分别暴露于整个柴油排气或超铁浓缩的环境颗粒以评估效果 关于脂肪肝病发展和动脉粥样硬化在实验方案中的不同PMS 连续或间歇性暴露于PM。将在各种组织中分析中间分子途径 （肺，血液，肝脏，主动脉），尤其是涉及花生四烯酸代谢和抗氧化稳态的患者 回答。数据将与在牙槽和全身性的各种时间内获得的炎症终点集成 巨噬细胞。在两个目标中观察到的对比效应之间的比较将使关键识别 负责发育与解决慢性炎症的途径。在AIM 3中，LDL-R KO小鼠 将测试5-LO途径的5-LO或用药物抑制剂处理的5-LO治疗以评估 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理解 PM引起的毒性具有预防或治疗意义。