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，长期暴露于环境颗粒物（PM） 导致动脉粥样硬化恶化和心血管发病率和死亡率增加。我们已经表明 小鼠暴露于柴油机废气和超细颗粒物（PM< 0.18 µm）导致脂质过氧化作用增加 在肺和全身组织中，伴随着对血浆脂蛋白的影响，脂质代谢紊乱， 代谢、肝脂肪变性和动脉粥样硬化，所谓的心脏代谢综合征的所有组成部分。PM- 这些疾病的诱导被认为涉及炎症途径的慢性和持续活化。 然而，虽然长期暴露于< 2.5 µm的PM（PM2.5）已被报道会导致脂肪性肝炎，但我们 表明长期暴露于柴油机废气也会导致甘油三酯在肝脏中积累（脂肪变性）， 不含炎症成分，表明不同成分的PM可能具有不同的能力， 在慢性暴露后激活炎症通路。这个项目旨在剖析分子 与炎症的发展和进展相关的通路与炎症的抑制或消退。我们 中心假设是PM暴露通过促氧化剂和促炎剂促进心脏代谢毒性， 导致花生四烯酸代谢途径广泛失调的作用，伴随5-脂氧合酶的激活， 当这种激活持续时，它会压倒自我平衡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 脂肪性肝炎的症状2)剖析分子途径和有毒成分 参与脂肪性肝炎和动脉粥样硬化的发展和进展， 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，并探讨阻断该途径以减轻 心脏代谢毒性和缓解PM诱导的炎症。在目标1和2中，将LDL-R KO小鼠 分别暴露于整个柴油机排气或超细浓缩的环境颗粒物中，以评估效果 不同PM对脂肪肝和动脉粥样硬化发展的影响 连续或间歇暴露于PM。将在各种组织中分析干预分子途径 （肺、血液、肝脏、主动脉），尤其是涉及花生四烯酸代谢和抗氧化剂稳态的那些 应答将数据与在各种组织（肺泡和全身）中获得的炎症终点进行整合 巨噬细胞在两个目标中观察到的对比效应之间进行比较，将有助于确定关键的 负责慢性炎症发展与消退的途径。在目标3中，LDL-R KO小鼠 缺乏5-LO或用5-LO途径的药理学抑制剂治疗的患者将进行测试，以评估 5-LO活化在介导PM诱导的炎症中的作用。该项目将有助于更好地了解 具有预防或治疗意义的PM诱导毒性。