Fine particulate matter exposure and small cerebrovascular inflammation

摘要 痴呆症是公共卫生的一个重大挑战，没有有效的治疗。环境细颗粒物（PM） 暴露显著增加认知功能障碍和痴呆的风险，其机制主要是 未知动物研究表明，PM暴露显著损害认知， 学习能力没有明确的机制。小脑血管疾病显著有助于 血管性认知障碍和痴呆初步研究表明，PM暴露导致 显著的小脑血管炎症伴过量活性氧（ROS）产生， 与雄性野生型（WT）C57 BL/6小鼠血清TNF-α、IL-6和IL-1β显著升高相关。 虽然PM暴露也在雌性WT C57 BL/6小鼠中诱导了显著的脑血管炎症，但仅 IL-6和IL-1β而非TNF-α显著升高。用TNF-α而非IL-6处理雄性WT小鼠 或IL-1β在小脑血管中诱导显著的炎症，而在 PM暴露的雄性TNF-α缺陷小鼠的小脑血管。相反，女性WT的治疗 用IL-6处理的小鼠在脑血管系统中引发了显著的炎症，而用IL-6处理的小鼠没有炎症。 PM暴露的雌性IL-6缺陷小鼠的脑血管。数据显示，PM 暴露显著损害了雄性小鼠的记忆和学习能力， 用TNF-α缺乏预防（用特异性抗体治疗或TNF-α敲除）。因此本 项目被提出来测试新的假设，即“PM暴露引起显着的小 由于男性TNF-α和女性IL-6的产生增加而导致脑血管炎症， 导致认知功能障碍”。具体目的有三：1）检验TNF-α 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感染诱导的女性小脑血管炎症中起关键作用; 3） 探讨PM应激诱导TNF-α和IL-6产生的性别差异机制。老化 WT C57 BL/6小鼠（雄性和雌性）将暴露于PM。活性氧产生与脑微血管 将在PM暴露后的不同时间点定量评价炎症。脑MRI成像将 评价基线、1周（急性效应）和2个月（慢性效应）时的结构变化 PM暴露后。小鼠学习和记忆能力将在基线、2、4 PM暴露后8周。还将使用雄性TNF-α缺陷小鼠和雌性 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），以确定 机制（S）。本项目的数据将提供关于 PM暴露患者痴呆症发展和进展的机制，并帮助探索 预防和治疗与PM暴露相关的痴呆症的新方法。

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.