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: 10570917
• 负责人: Jesus Antonio Araujo
• 金额: $ 52.16万
• 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/10570917
• 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; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic; Critical Pathways; Data; Development; Diameter; 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; Macrophage; Mediating; Metabolic; Metabolic Pathway; Metabolism; Molecular; Morbidity - disease rate; Mus; Organ; Outcome; Oxidative Stress; Particulate; Particulate Matter; Pathway interactions; Phase; Plasma; Protocols documentation; Reactive Oxygen Species; 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; inhibitor; lipid metabolism; mRNA Expression; meter; mortality; particle; particle exposure; pharmacologic; 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