Fine particulate matter exposure and small cerebrovascular inflammation

摘要 如果没有有效的治疗，痴呆症是对公共卫生的重大挑战。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，其机制很大程度上是S 未知。动物研究表明，PM暴露会显著损害认知功能，并导致认知能力下降 没有明确定义机制的学习能力。小脑血管疾病对 血管认知障碍和痴呆症。初步研究表明，PM暴露会导致 伴有过量ROS产生的显著小规模脑血管炎症 与雄性野生型(WT)C57BL/6小鼠血清肿瘤坏死因子-α、IL-6和IL-1β显著升高的相关性。 虽然PM暴露也能引起雌性WT C57BL/6小鼠显著的脑血管炎症，但只有 IL-6和IL-1β显著升高，而不是肿瘤坏死因子-α显著升高。用肿瘤坏死因子-α治疗雄性WT小鼠，而不用IL-6 或IL-1β诱导小脑血管明显炎症，未见炎症反应。 PM暴露的雄性肿瘤坏死因子-α缺陷小鼠的小脑血管。相比之下，女性WT的治疗 携带IL-6的小鼠在脑血管系统中引发了显著的炎症，而在 PM暴露下雌性IL-6缺陷小鼠的脑血管。初步数据还表明，PM 暴露显著损害雄性小鼠的记忆和学习能力，这是有效的 用肿瘤坏死因子-α缺乏(通过特异性抗体治疗或肿瘤坏死因子-α基因敲除)预防。因此，现在 该项目的提出是为了验证这一新的假设，即PM暴露会导致显著的 由于男性肿瘤坏死因子-α和女性IL-6的产生增加而导致的脑血管炎症， 导致认知功能障碍“。有三个具体目的：1)检验假设肿瘤坏死因子-α 中介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起关键作用；以及3) 探讨PM暴露诱导的肿瘤坏死因子-α和白介素6产生性别差异的机制。老龄化 WT C57BL/6小鼠(雄性和雌性)将暴露于PMROS产生与脑微血管 在PM暴露后的不同时间点将对炎症进行定量评估。脑核磁共振成像将 评估基线、1周(急性效应)和2个月(慢性效应)的结构变化 在PM暴露之后。小鼠的学习和记忆能力将在基线、2、4、 PM暴露后8周。研究还将使用雄性肿瘤坏死因子-α缺陷小鼠和雌性小鼠 IL-6受体缺陷小鼠以及巨噬细胞耗竭模型小鼠(雌雄)的确定 机制(S)。本项目的数据将提供有关 PM暴露患者痴呆的发生发展机制及有助于探讨 预防和治疗与PM暴露相关的痴呆的新方法。

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.