Dietary EPA mitigates ozone induced pulmonary inflammation through ChemR23 signaling

点击翻译按钮获取中文摘要

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.