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:
  • 金额:
    $ 54.89万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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Kymberly Mae Gowdy其他文献

Kymberly Mae Gowdy的其他文献

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{{ truncateString('Kymberly Mae Gowdy', 18)}}的其他基金

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:
    10563167
  • 财政年份:
    2020
  • 资助金额:
    $ 54.89万
  • 项目类别:
Dietary EPA mitigates ozone induced pulmonary inflammation through ChemR23 signaling
膳食 EPA 通过 ChemR23 信号传导减轻臭氧引起的肺部炎症
  • 批准号:
    10506938
  • 财政年份:
    2020
  • 资助金额:
    $ 54.89万
  • 项目类别:
Novel role for CD163 in ozone induced alterations of pulmonary immunity
CD163 在臭氧诱导的肺免疫改变中的新作用
  • 批准号:
    10170356
  • 财政年份:
    2018
  • 资助金额:
    $ 54.89万
  • 项目类别:
Novel role for CD163 in ozone induced alterations of pulmonary immunity
CD163 在臭氧诱导的肺免疫改变中的新作用
  • 批准号:
    10408766
  • 财政年份:
    2018
  • 资助金额:
    $ 54.89万
  • 项目类别:
Novel role for CD163 in ozone induced alterations of pulmonary immunity
CD163 在臭氧诱导的肺免疫改变中的新作用
  • 批准号:
    10158675
  • 财政年份:
    2018
  • 资助金额:
    $ 54.89万
  • 项目类别:
Novel role for CD163 in ozone induced alterations of pulmonary immunity
CD163 在臭氧诱导的肺免疫改变中的新作用
  • 批准号:
    9762914
  • 财政年份:
    2018
  • 资助金额:
    $ 54.89万
  • 项目类别:
Novel role for CD163 in ozone induced alterations of pulmonary immunity
CD163 在臭氧诱导的肺免疫改变中的新作用
  • 批准号:
    10290075
  • 财政年份:
    2018
  • 资助金额:
    $ 54.89万
  • 项目类别:
Novel role for CD163 in ozone induced alterations of pulmonary immunity
CD163 在臭氧诱导的肺免疫改变中的新作用
  • 批准号:
    10622014
  • 财政年份:
    2018
  • 资助金额:
    $ 54.89万
  • 项目类别:

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