Lovelace Respiratory Research Institute, Department of Environmental Toxicology, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA.
Am J Respir Crit Care Med. 2011 Jul 1;184(1):82-91. doi: 10.1164/rccm.201012-1967OC. Epub 2011 Apr 14.
To determine vascular signaling pathways involved in inhaled air pollution (vehicular engine emission) exposure-induced exacerbation of atherosclerosis that are associated with onset of clinical cardiovascular events.
To elucidate the role of oxidized low-density lipoprotein (oxLDL) and its primary receptor on endothelial cells, the lectin-like oxLDL receptor (LOX-1), in regulation of endothelin-1 expression and matrix metalloproteinase activity associated with inhalational exposure to vehicular engine emissions.
Atherosclerotic apolipoprotein E knockout mice were exposed by inhalation to filtered air or mixed whole engine emissions (250 μg particulate matter [PM]/m(3) diesel + 50 μg PM/m(3) gasoline exhausts) 6 h/d for 7 days. Concurrently, mice were treated with either mouse IgG or neutralizing antibodies to LOX-1 every other day. Vascular and plasma markers of oxidative stress and expression proatherogenic factors were assessed. In a parallel study, healthy human subjects were exposed to either 100 μg PM/m(3) diesel whole exhaust or high-efficiency particulate air and charcoal-filtered "clean" air (control subjects) for 2 hours, on separate occasions.
Mixed emissions exposure increased oxLDL and vascular reactive oxygen species, as well as LOX-1, matrix metalloproteinase-9, and endothelin-1 mRNA expression and also monocyte/macrophage infiltration, each of which was attenuated with LOX-1 antibody treatment. In a parallel study, diesel exhaust exposure in volunteer human subjects induced significant increases in plasma-soluble LOX-1.
These findings demonstrate that acute exposure to vehicular source pollutants results in up-regulation of vascular factors associated with progression of atherosclerosis, endothelin-1, and matrix metalloproteinase-9, mediated through oxLDL-LOX-1 receptor signaling, which may serve as a novel target for future therapy.
确定与临床心血管事件发生相关的参与吸入性空气污染（车辆发动机排放）暴露引起的动脉粥样硬化恶化的血管信号通路。
吸入性空气污染（车辆发动机排放）暴露与临床心血管事件的发生有关，但其潜在机制仍不清楚。氧化型低密度脂蛋白（oxLDL）及其在血管内皮细胞上的主要受体——凝集素样 oxLDL 受体（LOX-1）在调节与吸入性车辆发动机排放有关的内皮素-1 表达和基质金属蛋白酶活性方面起着重要作用。
载脂蛋白 E 基因敲除动脉粥样硬化小鼠经口鼻暴露于过滤空气或混合全发动机排放物（250μg 颗粒物质[PM]/m3 柴油+50μg PM/m3 汽油废气），每天 6 小时，持续 7 天。同时，每隔一天用小鼠 IgG 或 LOX-1 中和抗体对小鼠进行治疗。评估血管和血浆氧化应激标志物以及促动脉粥样硬化因子的表达。在一项平行研究中，健康的人类受试者分别暴露于 100μg PM/m3 柴油全废气或高效微粒空气和活性炭过滤的“清洁”空气（对照）中 2 小时。
混合排放物暴露增加了 oxLDL 和血管活性氧，以及 LOX-1、基质金属蛋白酶-9 和内皮素-1 mRNA 的表达，同时也增加了单核细胞/巨噬细胞浸润，这些都可以通过 LOX-1 抗体治疗来减轻。在一项平行研究中，志愿者人体暴露于柴油废气中会导致血浆可溶性 LOX-1 显著增加。
这些发现表明，车辆源污染物的急性暴露会导致与动脉粥样硬化进展相关的血管因子上调，包括内皮素-1 和基质金属蛋白酶-9，这是通过 oxLDL-LOX-1 受体信号转导介导的，这可能成为未来治疗的新靶点。
