The role of the lectin-like oxLDL receptor (LOX-1) in traffic-generated air pollution exposure-mediated alteration of the brain microvasculature in Apolipoprotein (Apo) E knockout mice.

Recent studies have shown a strong correlation between air pollution-exposure and detrimental out-comes in the central nervous system, including alterations in blood brain barrier (BBB) integrity, neuroinflammation, and neurodegeneration. However, the mechanisms mediating these pathologies have not yet been fully elucidated. We have previously reported that exposure to traffic-generated air pollution results in increased circulating oxidized low-density lipoprotein (oxLDL), associated with alterations in BBB integrity, in atherosclerotic Apolipoprotein E null (ApoE−/−) mice. Thus, we investigated the role of the lectin-like oxLDL receptor (LOX)-1 in mediating these deleterious effects in ApoE−/− mice exposed to a mixture of gasoline and diesel engine exhaust (MVE: 100 PM μg/m3) for 6h/d, 7d/week, for 30 d by inhalation. Concurrent with exposures, a subset of mice were treated with neutralizing anti-bodies to LOX-1 (LOX-1 Ab) i.p., or IgG (control) i.p., every other day during exposures. Resulting brain microvascular integrity, tight junction (TJ) protein expression, matrix metalloproteinase (MMP)-9/−2 activity, ROS, and markers of cellular adhesion and monocyte/macrophage sequestration were assessed. MVE-exposure resulted in decreased BBB integrity and alterations in microvascular TJ protein expression, associated with increased LOX-1 expression, MMP-9/−2 activities, and lipid peroxidation, each of which was attenuated with LOX-1 Ab treatment. Furthermore, MVE-exposure induced cerebral microvascular ROS and adhesion molecules, expression of which was not normalized through LOX-1 Ab-treatment. Such findings suggest that alterations in brain microvascular structure and integrity observed with MVE-exposure may be mediated, at least in part, via LOX-1 signaling.

近期研究表明，空气污染暴露与中枢神经系统的有害后果之间存在很强的相关性，包括血脑屏障（BBB）完整性的改变、神经炎症和神经退行性变。然而，介导这些病理的机制尚未完全阐明。我们之前曾报道，在动脉粥样硬化的载脂蛋白E缺失（ApoE - / -）小鼠中，暴露于交通产生的空气污染会导致循环中的氧化低密度脂蛋白（oxLDL）增加，并与血脑屏障完整性的改变有关。因此，我们通过吸入方式研究了凝集素样氧化低密度脂蛋白受体（LOX） - 1在ApoE - / -小鼠暴露于汽油和柴油发动机尾气混合物（MVE：100μg/m³颗粒物），每天6小时，每周7天，持续30天所介导的这些有害影响中的作用。在暴露的同时，一部分小鼠在暴露期间每隔一天腹腔注射中和性抗LOX - 1抗体（LOX - 1 Ab）或腹腔注射IgG（对照）。对由此产生的脑微血管完整性、紧密连接（TJ）蛋白表达、基质金属蛋白酶（MMP） - 9 / - 2活性、活性氧（ROS）以及细胞黏附和单核细胞/巨噬细胞隔离的标志物进行了评估。MVE暴露导致血脑屏障完整性降低和微血管TJ蛋白表达改变，同时伴有LOX - 1表达增加、MMP - 9 / - 2活性增加以及脂质过氧化，而这些情况在使用LOX - 1 Ab治疗后均得到缓解。此外，MVE暴露诱导了脑微血管ROS和黏附分子产生，其表达通过LOX - 1 Ab治疗未恢复正常。这些发现表明，MVE暴露所观察到的脑微血管结构和完整性的改变可能至少部分是通过LOX - 1信号传导介导的。