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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.

项目总结