Dietary DHA mitigates ozone induced pulmonary inflammation

膳食 DHA 可减轻臭氧引起的肺部炎症

基本信息

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
项目类别：
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

项目摘要

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 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.

项目概要前提和假设：臭氧 (O3) 是一种标准空气污染物，会增加慢性病的发病率肺部疾病对 O3 暴露造成的疼痛健康影响部分是通过肺部发生的。由肺泡巨噬细胞产生细胞因子/趋化因子 O3 诱导的炎症引发的炎症。肺泡巨噬细胞中的 TLR4 是由 Toll 样受体 4 (TLR4) 驱动的，可增加 NFκB 激活并因此，靶向 TLR4 驱动的信号传导。肺泡巨噬细胞是减轻 O3 引起的肺部炎症的可行靶点。应用中，我们重点关注饮食在调节肺泡巨噬细胞TLR4介导的作用暴露于 O3 后的炎症反应具体来说是膳食二十二碳六烯酸 (DHA)。西方饮食中很少摄入的 omega-3 多不饱和脂肪酸可以预防 O3- 基于强有力的初步数据，我们提出了中心假设。 DHA 通过两种不同的机制抑制和解决肺部炎症：1) 从结构上来说，我们认为质膜的 DHA 酰基链重塑了肺泡的大小和组成巨噬细胞脂筏抑制下游信号传导和细胞因子分泌 2) 生化，DHA；经过酶促转化为专门的促溶解脂质介质 (SPM)，因此，DHA 衍生的 SPM 会降低 NFκB 的激活。以及促炎细胞/趋化因子的产生，同时促进细胞凋亡的清除该假设得到了初步数据的支持，表明 DHA 存在。减少小鼠 O3 诱导的肺部炎症，增加 SPM 水平，同时增加 SPM 受体 ALX/FPR2 的表达，并在体外重塑脂筏大小。定义 DHA 的结构和生化机制，我们在目标 1 中提出了三个目标。将证明 DHA 通过以下方式改善 O3 诱导的肺部炎症和损伤消退使用 DHA 补充剂和 DHA 缺乏的小鼠在目标 2 中，我们将建立机制。 DHA 通过重塑肺泡巨噬细胞脂筏的生物物理结构来抑制在目标 3 中，我们将建立使用尖端定量成像方法的下游信号传导。 DHA 如何通过产生 SPM（包括使用 ALX/FPR 敲除小鼠所提出的目标将创新性地合并吸入。毒理学、营养生物化学、膜生物物理学和免疫学。完成该提案将：1）为临床 DHA 补充提供科学依据减轻 O3 引起的发病率的研究；2) 提供了之间的关键机制联系环境污染物暴露和饮食将为有针对性的治疗策略提供信息。其应用具有高度优先性，因为它为长期改善饮食奠定了基础为空气污染未达标地区的易感人群减轻损害提出建议健康影响。