Mechanisms of airborne particulate matter induced thrombosis

空气颗粒物诱发血栓形成的机制

• 批准号: 7163087
• 负责人: Gokhan M. Mutlu
• 金额: $ 53.8万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163087
• 关键词: adrenergic receptor; air pollution; alveolar macrophages; blood coagulation; cardiovascular disorder epidemiology; free radical oxygen; gene deletion mutation; gene targeting; genetically modified animals; interleukin 6; laboratory mouse; particle; protein structure function; respiratory epithelium; thrombosis

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.

描述（申请人提供）： 环境参与物质（PM）空气污染对心肺发病率和死亡率产生了重大贡献。有强大的流行病学数据将每天的环境PM与心肺疾病的住院治疗联系起来，并每天的心血管死亡率率。急性暴露于PM的水平增加也与急性心肌梗塞和缺血性中风的风险增加有关。但是，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。动物和人类暴露于PM会改变止血；增加纤维蛋白原和von Willebrand因子的水平，并诱导周围动脉血栓形成。为了支持PM引起的促血栓性状态，我们最近观察到，从杜塞尔多夫（Dusseldorf）收集的良好特征的PM暴露于德国的环境空气，导致出血，凝血酶原和部分凝血酶素的缩短，并增加了血小板计数以及血小板计数以及血小板计数以及血小板计数和因子VIII的水平。此外，小鼠暴露于PM增加了IL-6的支气管肺泡灌洗液水平，从而促进凝血并增强血小板的产生和凝血酶形成。因此，我们发现在暴露于PM后24小时增加血管内凝血酶的产生。在靶向缺失的IL-6的小鼠中废除了PM暴露对凝血酶形成的影响。同样，IL-6的重要调节剂抑制β-肾上腺素能受体会减弱PM诱导的凝血酶产生。 PM诱导的炎症刺激和细胞因子释放已被认为是由于上皮细胞和巨噬细胞产生活性氧（ROS）。这些新发现导致我们假设PM导致IL-6释放，从而通过ROS依赖性机制引起了超凝的状态。为了检验我们的假设，我们建议（1）确定PM诱导的IL-6产生和所得的超凝结状态是由肺泡巨噬细胞，肺泡上皮细胞还是两者兼而有之介导ROS的IL-6产生和由此产生的超凝状态需要，（3）确定β-肾上腺素能受体在PM诱导的IL-6产生和超凝蛋白状态的调节中的作用。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疗法，以减少PM引起的心血管事件和死亡率。