Dietary EPA mitigates ozone induced pulmonary inflammation through ChemR23 signaling

膳食 EPA 通过 ChemR23 信号传导减轻臭氧引起的肺部炎症

• 批准号: 10506938
• 负责人: Kymberly Mae Gowdy
• 金额: $ 14.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-20 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10506938
• 关键词: Acute; Adverse effects; Air Pollutants; Air Pollution; Alveolar Macrophages; Anabolism; Binding; Bronchoalveolar Lavage Fluid; CMKLR1 gene; Cell Count; Cells; Chronic lung disease; Clinical; Clinical Research; Consumption; Data; Dendritic Cells; Diet; Dietary Practices; Disease; Eicosapentaenoic Acid; Environmental Air Pollutants; Environmental Health; Enzyme-Linked Immunosorbent Assay; Esters; FDA approved; Family; Fatty Acids; Female; Fishes; G-Protein-Coupled Receptors; Gas Chromatography; Genetic; Health; Homeostasis; Immune; Immune response; Immunology; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Knock-out; Knockout Mice; Laboratories; Lead; Leukotrienes; Link; Lipid Biochemistry; Lung; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Mediterranean Diet; Molecular; Mononuclear; Morbidity - disease rate; Mus; N-3 polyunsaturated fatty acid; Natural Killer Cells; Nutrient; Omega-3 Fatty Acids; Outcome; Ozone; Parents; Pathway interactions; Peripheral; Phagocytosis; Pharmacology; Phase; Population; Process; Production; Prostaglandins; Proteins; Pulmonary Inflammation; Reporting; Resolution; Role; Series; Signal Transduction; Supplementation; Testing; Therapeutic; Thromboxanes; Tissues; Triglycerides; Water; air treatment; base; cardiovascular disorder risk; chemokine; cytokine; dietary; epidemiology study; human model; improved; innovation; lipid metabolism; lipidome; lung injury; macrophage; male; nutrition; ozone exposure; pollutant; preclinical study; receptor; response; western diet

PROJECT SUMMARY Premise and hypothesis: Ozone (O3) is a criteria air pollutant that increases the incidence of chronic pulmonary diseases. The detrimental health effects upon O3 exposure occur in part through pulmonary inflammation characterized by the production of cytokine/chemokines, suppression of alveolar macrophage phagocytosis, and influx of inflammatory cells into the lung. At a molecular level, one of the ways O3 initiates pulmonary inflammation is by altering lipid metabolism through increasing the biosynthesis of prostaglandins and leukotrienes and decreasing the production of specialized pro-resolving mediators (SPMs). SPMs are critical immunoresolvants with dual actions (i.e. they stop inflammation and trigger the resolution phase of inflammation). Recently we have reported that O3 exposure leads a suppression in select SPMs and if pulmonary levels are restored, pulmonary inflammation was reduced. Therefore, targeting SPM production is a viable target to mitigate O3-induced pulmonary inflammation. In this application, we focus on the role of diet in regulating pulmonary SPM production and the binding of these SPMs to receptors known to have downstream signaling that blocks inflammatory responses upon O3 exposure. Specifically, dietary eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid that is poorly consumed in the western diet, may protect against O3-induced pulmonary inflammation. EPA is the parent fatty acid that is metabolized to produce the SPM family resolvin E (RvE) series. RvE1 is has been shown to be beneficial in resolving inflammation, restoring tissue homeostasis, and deficiencies in RvE1 leads to the progression of multiple inflammatory diseases. RvE1, in particular, binds the G-protein coupled receptor ERV1/ChemR23. Based on strong preliminary data, we propose the central hypothesis that EPA blunts O3-induced pulmonary inflammation and promotes resolution of injury through the downstream activation of the RvE1-ChemR23 axis. The hypothesis is supported by preliminary data to show that O3 exposure reduces pulmonary expression of ChemR23, ChemR23 deficient mice have more lung inflammation following exposure, and augmenting RvE1 levels mitigates O3-induced pulmonary inflammation/injury. Approach: To define the role of dietary EPA in lung inflammation and injury following O3, we propose two independent aims. In Aim 1, we will demonstrate that dietary EPA improves O3-induced pulmonary inflammation and resolution of injury through the RvE1-ChemR23 axis utilizing EPA/RvE1 supplementation and a ChemR23-deficient mouse. In Aim 2, we will establish that dietary EPA remodels the pulmonary lipidome during O3-induced pulmonary inflammation/resolution of inflammation through the production of RvE1. The proposed aims will innovatively merge nutrition, environmental health, lipid biochemistry, and immunology. Impact: Completion of this proposal will: 1) provide the scientific rationale for clinical EPA supplementation studies mitigating O3-induced morbidity and; 2) provide mechanistic links between pollutant exposure and diet to inform therapeutic strategies.

项目摘要 前提和假设：臭氧（O3）是一种标准空气污染物，可增加慢性肺的发生率 疾病。 O3暴露对健康的不利影响部分通过肺部炎症发生 以细胞因子/趋化因子的产生为特征，抑制肺泡巨噬细胞吞噬作用， 和炎症细胞流入肺部。在分子水平上，O3启动肺的一种方式之一 炎症是通过增加前列腺素和 白第三种并减少专门的促进介质（SPM）的产生。 SPM很关键 具有双重动作的免疫防护剂（即它们阻止炎症并触发了分辨率阶段 炎）。最近，我们报道了O3暴露会导致选择SPM的抑制作用，以及 恢复肺部水平，减少肺部炎症。因此，针对SPM生产是一个 可行的靶标可减轻O3诱导的肺部炎症。在此应用中，我们专注于饮食在 调节肺SPM产生和这些SPM与已知下游的受体结合 信号会阻止O3暴露时炎症反应。具体而言，饮食中的eicosapentaenoic酸 （EPA）是一种在西方饮食中消耗不良的omega-3多不饱和脂肪酸，可以防止 O3诱导的肺部炎症。 EPA是代谢产生SPM的母脂肪酸 Family Resolvin E（RVE）系列。 RVE1已被证明有益于解决炎症，恢复 组织稳态和RVE1中的缺陷导致多种炎症性疾病的发展。 RVE1特别是结合G蛋白偶联受体ERV1/ChemR23。基于强大的初步数据 我们提出了一个中心假设，即EPA钝化O3诱导的肺部炎症并促进 通过RVE1-CHEMR23轴的下游激活损伤的分辨率。该假设是 在初步数据的支持下，O3暴露降低了Chemr23的肺表达 暴露后ChemR23缺乏的小鼠具有更多的肺部炎症，并增加了RVE1水平 减轻O3诱导的肺部炎症/损伤。方法：定义饮食EPA在肺中的作用 O3后的炎症和伤害，我们提出了两个独立的目标。在AIM 1中，我们将证明 饮食EPA改善了O3引起的肺部炎症和通过RVE1-CHEMR23的损伤解决 利用EPA/RVE1补充和ChemR23缺陷小鼠的轴。在AIM 2中，我们将确定 饮食EPA在O3诱导的肺部炎症/分辨率中重塑肺脂肪组 通过RVE1的生产发炎。拟议的目标将创新合并营养， 环境健康，脂质生物化学和免疫学。影响：该提案的完成将：1） 为临床EPA补充研究提供了科学原理，以减轻O3引起的发病率 和; 2）提供污染物暴露和饮食之间的机械联系，以告知治疗策略。