Mechanisms of airborne particulate matter induced thrombosis

空气颗粒物诱发血栓形成的机制

基本信息

批准号：
7488598
负责人：
Gokhan M. Mutlu
金额：
$ 37.65万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/7488598
关键词：
Activated Partial Thromboplastin Time measurement Acute Acute myocardial infarction Address Adrenergic Receptor Air Air Pollution Airborne Particulate Matter Alveolar Alveolar Macrophages Animal Model Animals Attenuated Blood Platelets Bone Marrow Brain hemorrhage Bronchoalveolar Lavage Fluid Cardiopulmonary Cardiovascular system Cells Chimera organism Clinical Coagulation Process Daily Data Development Dichloromethylene Diphosphonate Electron Transport Epithelial Cells Event Experimental Designs Exposure to Factor VIII Fibrinogen Generations Genetic Techniques Germany Health Hemorrhage Hemostatic function Hospitalization Hour Human In Vitro Inflammation Interleukin-6 Ischemic Stroke Knockout Mice Lead Link Liposomes Measurement Mediating Mitochondria Molecular Genetics Morbidity - disease rate Mus NADPH Oxidase Pathologic Peripheral Physiological Platelet Count measurement Production Prothrombin Pulmonary Heart Disease Rate Reactive Oxygen Species Research Personnel Risk Role Signal Transduction Source System Testing Thrombin Thrombosis Time Series Analysis Transgenic Animals Translations beta-adrenergic receptor cytokine design human disease macrophage mortality novel particle programs reconstitution research study von Willebrand Factor

项目摘要

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（由申请人提供）：环境参与物质（PM）空气污染对心肺发病率和死亡率有显着影响。有强有力的流行病学数据将每日环境 PM 水平与心肺疾病住院率和每日心血管死亡率联系起来。急性暴露于PM水平升高还与急性心肌梗死和缺血性中风的风险增加相关。然而，PM 引发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。动物和人类接触 PM 会改变止血作用；增加纤维蛋白原和血管性血友病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，将小鼠暴露于从德国杜塞尔多夫周围空气中收集的特征明确的 PM 会导致出血、凝血酶原和部分凝血活酶时间缩短，并增加血小板计数和凝血酶原时间。因子 VIII 的水平。此外，小鼠暴露于 PM 会增加支气管肺泡灌洗液中 IL-6 的水平，从而促进凝血并增强血小板生成和凝血酶形成。因此，我们发现暴露于 PM 24 小时后血管内凝血酶的生成增加。在靶向删除 IL-6 的小鼠中，PM 暴露对凝血酶形成的影响被消除。同样，抑制β-肾上腺素能受体（IL-6 的重要调节剂）会减弱 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 (ROS) 所致。这些新发现使我们推测 PM 会导致 IL-6 释放，从而通过 ROS 依赖性机制导致高凝状态。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介导，(2) 确定 PM 诱导的产生是否由肺泡巨噬细胞、肺泡上皮细胞介导ROS 是 IL-6 产生和由此产生的高凝状态所必需的，并且 (3) 确定 β-肾上腺素能受体在调节 PM 诱导的 IL-6 产生中的作用和高凝状态。我们提出的研究解决了一个重要的人类健康问题，并可能导致新疗法的开发，以减少 PM 引起的心血管事件和死亡率。