Mechanisms of airborne particulate matter induced thrombosis

空气颗粒物诱发血栓形成的机制

• 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
• 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

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）： 大气颗粒物（PM）污染是导致心肺疾病发病率和死亡率的重要因素。有强有力的流行病学数据将环境PM的每日水平与心肺疾病的住院率和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诱发这些病理事件和增加心血管死亡率的机制在很大程度上是未知的。动物和人类暴露于PM会改变止血;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，小鼠暴露于从德国杜塞尔多夫的环境空气中收集的表征良好的PM，导致出血、凝血酶原和部分凝血活酶时间缩短，血小板计数和因子VIII水平增加。此外，小鼠暴露于PM增加了支气管肺泡灌洗液中IL-6的水平，IL-6促进凝血并增强血小板生成和凝血酶形成。因此，我们发现，血管内凝血酶的产生增加暴露于PM后24小时。PM暴露对凝血酶形成的影响在IL-6靶向缺失的小鼠中被消除。同样，β-肾上腺素能受体，一个重要的调节IL-6，衰减PM诱导的凝血酶生成的抑制。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）。这些新发现使我们假设PM引起IL-6释放，其通过ROS依赖性机制引起高凝状态。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介导，（2）确定PM诱导的ROS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，并可能导致新疗法的开发，以减少PM诱导的心血管事件和死亡率。