Exposure to traffic-generated air pollutants mediates alterations in brain microvascular integrity in wildtype mice on a high-fat diet.

Air pollution-exposure is associated with detrimental outcomes in the central nervous system (CNS) such as cerebrovascular disorders, including stroke, and neurodegenerative diseases. While the mechanisms of these CNS-related outcomes involved have not been fully elucidated, exposure to traffic-generated air pollutants has been associated with altered blood brain barrier (BBB) integrity and permeability. The current study investigated whether inhalation exposure to mixed vehicle emissions (MVE) alters cerebral microvascular integrity in healthy 3 mo old C57BL/6 mice, as well as whether exposure-mediated effects were exacerbated by a high-fat (HF) vs. low-fat (LF) diet. Mice on each diet were randomly assigned to be exposed to either filtered air (FA) or MVE [100 PM/m3 vehicle emissions mixture: 30 µg PM/m3 gasoline engine + 70 µg PM/m3 diesel engine emissions; median size ∼60 nm; particle mass size distribution median of ∼1 µm (range: <0.5 – 20µm)] for 6 hr/d, 7d/wk, for 30d. Using sodium fluorescein as a tracer, we observed a significant increase in BBB permeability in both HF+MVE exposed and HF+FA animals, compared to LF+FA controls. Exposure to HF+MVE also led to a significant increase plasma ox-LDL and ox-LDL scavenger receptors (LOX-1 and CD-36) expression in the cerebral vasculature. Histological analysis revealed decreased expression of TJ protein, claudin-5, associated with increased matrix metalloproteinase (MMP)-9 activity and oxidative stress in the cerebral vasculature of HF+MVE mice, compared to LF+MVE. Such findings indicate that inhalation exposure to traffic-generated pollutants, coupled with a HF diet, results in altered BBB integrity and increased ox-LDL signaling in the cerebral vasculature in a wildtype animal model.

空气污染暴露与中枢神经系统（CNS）的有害后果相关，例如脑血管疾病（包括中风）和神经退行性疾病。虽然所涉及的这些与中枢神经系统相关后果的机制尚未完全阐明，但暴露于交通产生的空气污染物与血脑屏障（BBB）完整性和通透性的改变有关。当前的研究调查了吸入混合机动车排放物（MVE）是否会改变3月龄健康C57BL/6小鼠的脑微血管完整性，以及高脂肪（HF）饮食与低脂肪（LF）饮食相比是否会加剧暴露介导的影响。每种饮食的小鼠被随机分配暴露于过滤空气（FA）或MVE[100微克/立方米机动车排放混合物：30微克/立方米汽油发动机排放物 + 70微克/立方米柴油发动机排放物；中值粒径约60纳米；颗粒质量粒径分布中值约1微米（范围：<0.5 - 20微米）]，每天6小时，每周7天，持续30天。使用荧光素钠作为示踪剂，我们观察到与LF + FA对照组相比，HF + MVE暴露组和HF + FA组动物的血脑屏障通透性均显著增加。暴露于HF + MVE还导致脑血管中血浆氧化低密度脂蛋白（ox - LDL）以及氧化低密度脂蛋白清道夫受体（LOX - 1和CD - 36）的表达显著增加。组织学分析显示，与LF + MVE相比，HF + MVE小鼠脑血管中紧密连接蛋白克劳丁 - 5的表达降低，同时伴有基质金属蛋白酶（MMP）- 9活性和氧化应激增加。这些发现表明，在野生型动物模型中，吸入交通产生的污染物，再加上高脂肪饮食，会导致血脑屏障完整性改变以及脑血管中氧化低密度脂蛋白信号增加。