Mechanisms of airborne particulate matter induced thrombosis

描述(由申请人提供)： 环境参与物质(PM)空气污染对心肺疾病的发病率和死亡率有很大影响。有强有力的流行病学数据将环境PM的每日水平与因心肺疾病住院和每日心血管死亡率联系起来。急性暴露于PM水平升高也与急性心肌梗死和缺血性中风的风险增加有关。然而，PM引起这些病理事件并增加心血管死亡率的机制在很大程度上尚不清楚。动物和人类暴露在PM下会改变止血；增加纤维蛋白原和von Willebrand因子的水平，并诱导外周动脉血栓形成。为了支持PM诱导的血栓前状态，我们最近观察到，在德国杜塞尔多夫，小鼠暴露在从环境空气中收集的具有良好特征的PM中，可以缩短出血、凝血酶原和部分凝血活酶时间，增加血小板计数和第VIII因子水平。此外，小鼠暴露在PM中，增加了支气管肺泡灌洗液中IL-6的水平，促进了凝血，促进了血小板的生成和凝血酶的形成。因此，我们发现PM暴露24小时后血管内凝血酶的生成增加通过靶向删除IL-6，PM暴露对小鼠凝血酶形成的影响被取消。同样，抑制β-肾上腺素能受体--IL-6的重要调节因子--可减弱PM诱导的凝血酶生成。PM诱导的炎症刺激和细胞因子释放被认为是由于上皮细胞和巨噬细胞产生活性氧物种(ROS)所致。这些新的发现导致我们假设PM导致IL-6的释放，而IL-6通过ROS依赖的机制导致高凝状态。为了验证我们的假设，我们建议(1)确定PM诱导的IL-6产生和由此产生的高凝状态是否由肺泡巨噬细胞、肺泡上皮细胞或两者共同介导，(2)确定PM诱导的ROS的产生是否是IL-6产生和由此产生的高凝状态所必需的，以及(3)确定β-肾上腺素能受体在PM诱导的IL-6产生和高凝状态调节中的作用。我们提出的研究解决了一个重要的人类健康问题，并可能导致开发新的治疗方法，以减少PM引起的心血管事件和死亡率。

DESCRIPTION (provided by the applicant): Ambient participate matter (PM) air pollution contributes significantly to cardiopulmonary morbidity and mortality. There are strong epidemiologic data that link daily levels of ambient PM to hospitalizations for cardiopulmonary disease and daily rates of cardiovascular mortality. Acute exposure to increased levels of PM is also associated with increased risk of acute myocardial infarction, and ischemic stroke. However, the mechanisms by which PM elicits these pathologic events and increases cardiovascular mortality are largely unknown. Exposure of animals and humans to PM alters hemostasis; increasing the levels of fibrinogen, and von Willebrand factor and inducing peripheral arterial thrombosis. In support of a PM-induced prothrombotic state, we have recently observed that exposure of mice to well-characterized PM collected from ambient air in Dusseldorf, Germany caused shortening of the bleeding, prothrombin and partial thromboplastin times, and increased the platelet count and the levels of factor VIII. Moreover, exposure of mice to PM increased bronchoalveolar lavage fluid levels of IL-6, which promotes coagulation and enhances platelet production and thrombin formation. Accordingly, we found that generation of intravascular thrombin was increased 24 hours after exposure to PM. The effect of PM-exposure on thrombin formation was abrogated in mice with targeted deletion of IL-6. Similarly, inhibition of beta-adrenergic receptors, an important regulator of IL-6, attenuated PM-induced thrombin generation. PM-induced stimulation of inflammation and cytokine release has been suggested to be due to the generation of reactive oxygen species (ROS) by epithelial cells and macrophages. These new findings led us to hypothesize that PM causes IL-6 release, which causes a hyper-coagulable state via a ROS-dependent mechanism. To test our hypothesis, we propose to (1) determine whether PM-induced IL-6 production and the resultant hyper-coagulable state are mediated by alveolar macrophages, alveolar epithelial cells, or both, (2) determine whether the PM-induced generation of ROS is required for IL-6 production and the resultant hyper-coagulable state, and (3) determine the role of beta-adrenergic receptors in modulation of the PM-induced IL-6 production and hyper-coagulable state. The studies we are proposing address an important human health problem and could lead to the development of novel therapies to diminish PM-induced cardiovascular events and mortality.