Dietary DHA mitigates ozone induced pulmonary inflammation

膳食 DHA 可减轻臭氧引起的肺部炎症

• 批准号: 10360534
• 负责人: Kymberly Mae Gowdy
• 金额: $ 54.89万
• 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/10360534
• 关键词: Acute; Adverse effects; Air Pollutants; Air Pollution; Alveolar Macrophages; Apoptotic; Area; Biochemical; Biophysics; Cell membrane; Cells; Cholesterol; Chronic lung disease; Clinical; Complex; Consumption; Data; Diet; Dietary Administration; Docosahexaenoic Acids; Docosahexaenoic acid supplement; Docosahexaenoic acid supplementation; Environmental Pollutants; Exposure to; FPR2 gene; Health; Immunology; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Inhalation Toxicology; Injury; Intake; Knockout Mice; Link; Lung; Mediating; Membrane; Membrane Microdomains; Microscopy; Morbidity - disease rate; Mus; Nutrient; Nutritional Biochemistry; Omega-3 Fatty Acids; Outcome; Ozone; Phenotype; Population; Production; Public Health; Pulmonary Inflammation; Recommendation; Reporting; Resolution; Role; Signal Transduction; Sorting - Cell Movement; Source; Structure; TLR4 gene; Testing; Therapeutic; air filter; base; chemokine; cytokine; dietary; human model; imaging approach; improved; innovation; lipid mediator; lipidomics; lung injury; macrophage; methyl-beta-cyclodextrin; multidisciplinary; novel therapeutic intervention; ozone exposure; prevent; quantitative imaging; receptor; recruit; targeted treatment; 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 initiated by alveolar macrophage production of cytokine/chemokines. O3-induced inflammation in the alveolar macrophage is driven by toll-like receptor 4 (TLR4), that increases NFB activation and subsequent production of proinflammatory cytokines. Therefore, targeting TLR4 driven signaling in alveolar macrophages is a viable target to mitigate O3-induced pulmonary inflammation. In this application, we focus on the role of diet in regulating alveolar macrophage TLR4-mediated inflammatory responses upon O3 exposure. Specifically, dietary docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid that is poorly consumed in the western diet, may protect against O3- induced pulmonary inflammation. Based on strong preliminary data, we propose the central hypothesis that DHA suppresses and resolves pulmonary inflammation through two distinct mechanisms: 1) Structurally, we propose that DHA acyl chains of the plasma membrane remodel the size and composition of alveolar macrophage lipid rafts to suppress downstream signaling and cytokine secretion; 2) Biochemically, DHA undergoes enzymatic conversion into specialized pro-resolving lipid mediators (SPM), which are highly potent immunoresolvants. As a consequence, DHA-derived SPMs decrease NFB activation and the production of proinflammatory cyto/chemokines while promoting the clearance of apoptotic cells termed ‘efferocytosis’. The hypothesis is supported by preliminary data to show that DHA decreases murine O3 induced pulmonary inflammation, augments levels of SPMs while increasing expression of the SPM receptor ALX/FPR2, and remodels lipid raft size in vitro. Approach: To define the structural and biochemical mechanisms of DHA, we propose three aims. In Aim 1, we will demonstrate that DHA improves O3-induced pulmonary inflammation and resolution of injury through the use of DHA supplementation and a DHA-deficient mouse. In Aim 2, we will establish the mechanism by which DHA remodels the biophysical structure of lipid rafts of alveolar macrophages to suppress downstream signaling using cutting-edge quantitative imaging approaches. In Aim 3, we will establish how DHA improves O3-induced pulmonary inflammation through the production of SPMs including the use of an ALX/FPR knockout mouse. The proposed aims will innovatively merge inhalation toxicology, nutritional biochemistry, membrane biophysics, and immunology. Impact: Completion of this proposal will: 1) provide the scientific rationale for clinical DHA supplementation studies mitigating O3-induced morbidity and; 2) provide key mechanistic links between environmental pollutant exposure and diet that will inform targeted therapeutic strategies. Collectively, this application is of high priority given that it sets the basis for long-term improved dietary recommendations for susceptible populations in nonattainment air pollution areas to mitigate detrimental health effects.

项目摘要 前提和假设：臭氧（O3）是一种标准空气污染物，可增加慢性的发生率 肺部疾病。 O3暴露的不利健康影响部分通过肺部发生 通过肺泡巨噬细胞的产生细胞因子/趋化因子引发的炎症。 O3引起的炎症 在肺泡巨噬细胞中，巨噬细胞由Toll样受体4（TLR4）驱动，这会增加NFB的激活和 随后产生促炎细胞因子。因此，针对TLR4驱动信号传导 肺泡巨噬细胞是减轻O3诱导的肺注射的可行靶标。在这个 应用，我们专注于饮食在确定肺泡巨噬细胞TLR4介导的作用 O3暴露时炎症反应。具体而言，饮食二十二碳六烯酸（DHA）， 在西部饮食中消耗率不高的omega-3多不饱和脂肪酸可能会预防O3-- 诱导肺部炎症。基于强大的初步数据，我们提出了中心假设 DHA通过两种不同的机制抑制并解析了肺注射：1）结构上， 我们提出质膜重塑的DHA酰基链大小和牙槽的组成 巨噬细胞脂质筏抑制下游信号传导和细胞因子分泌； 2）生化，DHA 将酶转化为专门的促脂脂质介质（SPM）， 高潜力的免疫抗物剂。结果，DHA衍生的SPMS减少NFB激活 以及促进凋亡清除率的促炎细胞/趋化因子的产生 细胞称为“肿瘤病”。该假设由初步数据支持，以表明DHA 减少鼠O3诱导的肺注射，增强SPM的水平，同时增加 SPM受体ALX/FPR2的表达，并在体外重塑脂质筏大小。方法： 定义DHA的结构和生化机制，我们提出了三个目标。在AIM 1中，我们 将证明DHA可以改善O3诱导的肺注射和通过 使用补充DHA和DHA缺陷小鼠。在AIM 2中，我们将建立机制 DHA重塑肺泡巨噬细胞脂质筏的生物物理结构以抑制 使用尖端定量成像方法的下游信号传导。在AIM 3中，我们将建立 DHA如何通过生产SPM的生产（包括） 使用ALX/FPR基因敲除鼠标。拟议的目标将创新合并事故 毒理学，营养生物化学，膜生物物理学和免疫学。影响： 该提案的完成将：1）提供临床DHA补充的科学原理 研究减轻O3引起的发病率和； 2）提供关键的机械链接 环境污染物的暴露和饮食将为有针对性的治疗策略提供信息。总的来说，这 鉴于它为长期改善饮食的基础设定了基础，因此优先级是优先的 在非缔造空气污染区域中易感人群的建议，以减轻确定 健康影响。