Fine particulate matter exposure and small cerebrovascular inflammation

细颗粒物暴露与小脑血管炎症

• 批准号: 10807363
• 负责人: ZHENGUO LIU
• 金额: $ 215.13万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10807363
• 关键词: Acetylcysteine; Acute; Adhesives; Affective; Age; Aging; Air Pollution; Alzheimer' s Disease; Animals; Antibodies; Antibody Therapy; Area; C57BL/6 Mouse; Cardiovascular Diseases; Cells; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Chronic; Complex; Data; Dementia; Development; Diameter; Edema; Elderly; Endothelial Cells; Exposure to; FDA approved; Female; Hippocampus; Image; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Interleukin 6 Receptor; Interleukin-1 beta; Interleukin-6; Knock-out; Learning; Leukocytes; Macrophage; Mediating; Memory; Memory impairment; Mus; Oxidative Stress; Particulate Matter; Patients; Permeability; Pharmaceutical Preparations; Play; Population Study; Production; Public Health; Reactive Oxygen Species; Risk; Rodent; Role; Serum; Sex Differences; Source; TNF gene; Techniques; Testing; Time; Vascular Diseases; Wild Type Mouse; brain magnetic resonance imaging; brain tissue; cerebrovascular; cytokine; design; effective therapy; experimental study; fine particles; genetic approach; male; meter; mouse model; novel; novel strategies; particle; pharmacologic; postcapillary venule; preservation; prevent; response; vascular cognitive impairment and dementia; vascular inflammation

Abstract Dementia is a major challenge to public health without effective therapy. Ambient fine particulate matter (PM) exposure significantly increases the risk for cognitive dysfunction and dementia with the mechanism(s) largely unknown. Animal studies have revealed that PM exposure significantly impairs cognition with decreased learning capability without clearly defined mechanisms. Small cerebrovascular diseases significantly contribute to vascular cognitive impairment and dementia. Preliminary studies showed that PM exposure resulted in significant small cerebrovascular inflammation with excessive reactive oxygen species (ROS) production in association with significant increases in serum TNF-α, IL-6, and IL-1β in male wildtype (WT) C57BL/6 mice. While PM exposure also induced significant cerebral vascular inflammation in female WT C57BL/6 mice, only IL-6 and IL-1β, not TNF-α, were significantly increased. Treatment of male WT mice with TNF-α, but not IL-6 or IL-1β, induced significant inflammation in small cerebral vasculature, and no inflammation was observed in small cerebral vessels in male TNF-α deficient mice with PM exposure. In contrast, treatment of female WT mice with IL-6 triggered a significant inflammation in cerebral vasculature, and no inflammation was present in cerebral vessels in female IL-6 deficient mice with PM exposure. Initial data also demonstrated that PM exposure significantly impaired the memory and learning capability in male mice that were effectively prevented with TNF-α deficiency (either with specific antibody treatment or TNF-α knockout). Thus, the present project was proposed to test the novel hypothesis that “PM exposure induces significant small cerebrovascular inflammation due to increased production of TNF-α in males and IL-6 in females, leading to cognitive dysfunction”. There are three specific aims: 1) to test the hypothesis that TNF-α mediates the effect of PM exposure on small cerebrovascular inflammation in males; 2) to test the hypothesis that IL-6 plays a critical role in PM exposure-induced small cerebrovascular inflammation in females; and 3) to investigate the mechanisms for sex differences in PM exposure-induced productions of TNF-α and IL-6. Aging WT C57BL/6 mice (both male and female) will be exposed to PM. ROS production and cerebral microvascular inflammation will be quantitatively evaluated at different time points after PM exposure. Brain MRI imaging will be performed to evaluate structural changes at baseline, 1 week (acute effect), and 2 months (chronic effect) after PM exposure. Mouse learning and memory capability will be longitudinally evaluated at baseline, 2, 4, and 8 weeks after PM exposure. Studies will also be conducted using male TNF-α deficient mice and female IL-6 receptor deficient mice, as well as macrophage depletion mouse model (both male and female) to define the mechanism(s). The data from the present project will provide important and novel information on the mechanisms for the development and progression of dementia in patients with PM exposure and help explore new approaches to preventing and treating dementia related to PM exposure.

抽象的 如果没有有效的治疗方法，痴呆症将成为公共卫生面临的重大挑战。 接触显着增加认知功能障碍和痴呆的风险，其机制主要是 动物研究表明，PM 暴露会显着损害认知能力，并导致认知能力下降。 没有明确机制的学习能力对小脑血管疾病有显着影响。 初步研究表明，PM 暴露会导致血管性认知障碍和痴呆。 严重的小脑血管炎症，并伴有过多的活性氧（ROS）产生 与雄性野生型 (WT) C57BL/6 小鼠血清 TNF-α、IL-6 和 IL-1β 显着增加相关。 虽然 PM 暴露也会诱发雌性 WT C57BL/6 小鼠显着的脑血管炎症，但仅 用 TNF-α（而非 IL-6）治疗雄性 WT 小鼠，IL-6 和 IL-1β 显着增加。 或 IL-1β 诱导小脑血管炎症，但在 与 PM 暴露的雄性 TNF-α 缺陷小鼠的小脑血管相比，雌性 WT 的治疗。 具有 IL-6 的小鼠在脑血管系统中引发了显着的炎症，但在脑血管系统中不存在炎症。 暴露于 PM 的雌性 IL-6 缺陷小鼠的脑血管初步数据也表明 PM 存在。 暴露显着损害了雄性小鼠的记忆和学习能力 TNF-α 缺乏症可以预防（通过特异性抗体治疗或 TNF-α 敲除）。 提出该项目的目的是检验“PM 暴露会导致显着的小 由于男性 TNF-α 和女性 IL-6 产生增加而导致脑血管炎症， 导致认知功能障碍”，有三个具体目标：1）检验 TNF-α 的假设。 介导 PM 暴露对男性小脑血管炎症的影响 2) 检验假设； IL-6 在 PM 暴露引起的女性小脑血管炎症中发挥着关键作用；3) 研究 PM 暴露引起的 TNF-α 和 IL-6 衰老产生的性别差异机制。 WT C57BL/6 小鼠（雄性和雌性）将暴露于 ROS 产生和脑微血管。 将在 PM 暴露后的不同时间点对炎症进行定量评估。 用于评估基线、1 周（急性效应）和 2 个月（慢性效应）时的结构变化 PM 暴露后，将在基线、2、4 时纵向评估小鼠的学习和记忆能力。 以及 PM 暴露后 8 周，还将使用 TNF-α 缺陷的雄性小鼠和雌性小鼠进行研究。 IL-6受体缺陷小鼠以及巨噬细胞耗竭小鼠模型（雄性和雌性）来定义 当前项目的数据将提供有关该机制的重要且新颖的信息。 PM 暴露患者痴呆发生和进展的机制并有助于探索 预防和治疗与 PM 暴露相关的痴呆症的新方法。