Dietary DHA mitigates ozone induced pulmonary inflammation

项目总结 前提和假设：臭氧(臭氧)是一种标准的空气污染物，会增加慢性病的发病率 肺部疾病。接触臭氧对健康的有害影响部分通过肺部发生 由肺泡巨噬细胞产生细胞因子/趋化因子引起的炎症。臭氧致炎 在肺泡巨噬细胞中，Toll样受体4(TLR4)是由Toll样受体4驱动的，它增加了NFB的激活和 随后产生促炎细胞因子。因此，针对TLR4驱动的信令 肺泡巨噬细胞是减轻臭氧诱导的肺部炎症的有效靶点。在这 应用方面，我们重点介绍了饮食在调节肺泡巨噬细胞TLR4介导中的作用 臭氧暴露引起的炎症反应。具体地说，饮食中的二十二碳六烯酸(DHA)，一种 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-3 引起肺部炎症。基于强劲的初步数据，我们提出了中心假设 DHA通过两种不同的机制抑制和化解肺部炎症：1)结构上， 我们认为质膜上的DHA酰链重塑了肺泡的大小和组成。 巨噬细胞脂筏抑制下游信号和细胞因子分泌；2)生化方面，DHA 经过酶促转化为专门的促分解脂质介体(SPM)，这是 高效免疫解析剂。因此，DHA衍生的SPM会降低核因子B的活性 和促炎细胞/趋化因子的产生，同时促进细胞凋亡的清除 称为“胞吐”的细胞。这一假设得到了初步数据的支持，表明DHA 减少臭氧诱导的小鼠肺部炎症，增加SPM水平，同时增加 表达SPM受体ALX/FPR2，并在体外重塑脂筏大小。方法： 定义了DHA的结构和生化机制，提出了三个目标。在目标1中，我们 将证明DHA通过以下途径改善臭氧诱导的肺部炎症和损伤的解决 使用DHA补充剂和DHA缺陷小鼠。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 使用尖端定量成像方法的下行信号。在目标3中，我们将确立 DHA如何通过产生SPM改善臭氧诱导的肺部炎症 使用ALX/FPR基因敲除小鼠。提议的目标将创新性地合并吸入性 毒理学、营养生物化学、膜生物物理学和免疫学。影响： 这项建议的完成将：1)为临床补充DHA提供科学依据 减轻臭氧引起的发病率的研究；2)提供了关键的机制联系 环境污染物暴露和饮食，将提供有针对性的治疗策略。总而言之，这 应用是高度优先的，因为它为长期改善饮食奠定了基础 对未达标空气污染地区的易感人群提出建议，以减轻有害影响 对健康的影响。

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.