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 假设和假说：臭氧（O3）是一种标准空气污染物，可增加慢性肺疾病的发病率， 疾病暴露于O3对健康的有害影响部分是通过肺部炎症发生的 其特征在于产生细胞因子/趋化因子，抑制肺泡巨噬细胞吞噬作用， 以及炎症细胞流入肺部在分子水平上，O3引发肺部 炎症是通过增加洋地黄素的生物合成来改变脂质代谢， 白细胞三烯和减少生产的专业前解决调解人（SPM）。SPM至关重要 具有双重作用的免疫消退剂（即，它们停止炎症并触发炎症的消退阶段） 炎症）。最近，我们报道了O3暴露导致选择SPM的抑制，如果 肺部水平恢复，肺部炎症减轻。因此，以SPM生产为目标是 减轻O3诱导的肺部炎症的可行靶点。在这个应用程序中，我们关注饮食在以下方面的作用： 调节肺SPM的产生以及这些SPM与已知具有下游功能的受体的结合， 在暴露于O3时阻断炎症反应的信号传导。具体来说，饮食中的二十碳五烯酸 (EPA)在西方饮食中很少摄入的omega-3多不饱和脂肪酸， O3引起的肺部炎症。EPA是代谢产生SPM的母体脂肪酸 家族分解素E（RvE）系列。RvE 1已被证明有利于缓解炎症，恢复 组织内稳态和RvE 1的缺乏导致多种炎性疾病的进展。 RvE 1尤其结合G蛋白偶联受体ERV 1/ChemR 23。根据强有力的初步数据， 我们提出了一个中心假设，即EPA可以减弱O3诱导的肺部炎症， 通过RvE 1-ChemR 23轴的下游激活来解决损伤。这个假设是 由初步数据支持，表明O3暴露降低了ChemR 23的肺表达， ChemR 23缺陷小鼠在暴露后有更多的肺部炎症，并增加RvE 1水平 减轻O3诱导的肺部炎症/损伤。方法：确定膳食EPA在肺中的作用 炎症和损伤后O3，我们提出了两个独立的目标。在目标1中，我们将证明， 膳食EPA通过RvE 1-ChemR 23改善O3诱导的肺部炎症和损伤的消退 轴利用EPA/RvE 1补充和ChemR 23缺陷小鼠。在目标2中，我们将确定 膳食EPA在O3诱导的肺部炎症期间重塑肺脂质体/ 通过RvE 1的产生而引起炎症。拟议的目标将创新地将营养， 环境健康、脂质生物化学和免疫学。影响：完成本提案将：1） 为临床EPA补充研究减轻O3诱导的发病率提供科学依据 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。