Dietary EPA mitigates ozone induced pulmonary inflammation through ChemR23 signaling

项目总结 前提和假设：臭氧(O3)是一种标准的空气污染物，会增加慢性肺病的发病率 疾病。接触臭氧对健康的有害影响部分是通过肺部炎症发生的 以产生细胞因子/趋化因子，抑制肺泡巨噬细胞吞噬为特征， 以及炎症细胞涌入肺部。在分子水平上，臭氧启动肺脏的一种方式 炎症是通过增加前列腺素和前列腺素的生物合成来改变脂代谢。 白三烯和减少专门的促分解介体(SPM)的产生。SPM非常关键 具有双重作用的免疫解析剂(即它们停止炎症并触发 炎症)。最近，我们报道了臭氧暴露会导致特定SPM的抑制，如果 肺水平恢复，肺部炎症减轻。因此，瞄准SPM生产是一项 减轻臭氧引起的肺部炎症的可行靶点。在本应用程序中，我们重点介绍饮食在 调节肺SPM的产生以及这些SPM与已知有下游的受体的结合 发出信号，阻止接触臭氧时的炎症反应。具体地说，膳食二十碳五烯酸 (EPA)是一种在西方饮食中很少摄入的omega-3多不饱和脂肪酸，可能会预防 臭氧诱导的肺部炎症。EPA是代谢产生SPM的母体脂肪酸 家庭解决方案E(RVE)系列。RvE1已被证明在消炎、恢复 组织动态平衡和RvE1的缺陷会导致多种炎症性疾病的进展。 特别是，RvE1与G蛋白偶联受体ERV1/ChemR23结合。基于强劲的初步数据， 我们提出的中心假设是，EPA钝化臭氧诱导的肺部炎症并促进 通过RvE1-ChemR23轴的下游激活来解决损伤。假设是 初步数据表明，臭氧暴露降低了肺组织中ChemR23的表达， ChemR23缺陷小鼠在暴露后有更多的肺部炎症，并增加了RvE1水平 减轻臭氧引起的肺部炎症/损伤。方法：确定膳食EPA在肺中的作用 对于臭氧引起的炎症和损伤，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RvE1-ChemR23改善臭氧诱导的肺部炎症和损伤的缓解 利用EPA/RvE1补充的AXIS和缺乏ChemR23的小鼠。在目标2中，我们将确立 膳食EPA在臭氧诱导的肺部炎症/消退过程中重塑肺脂体 通过产生RvE1而产生的炎症。拟议的目标将创新性地合并营养， 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补充研究减轻臭氧引起的发病率提供科学依据 以及；2)提供污染物暴露和饮食之间的机械联系，为治疗策略提供参考。

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.