Mechanisms of airborne particulate matter induced thrombosis

空气颗粒物诱发血栓形成的机制

• 批准号: 7921554
• 负责人: Gokhan M. Mutlu
• 金额: $ 37.64万
• 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/7921554
• 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; 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; 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; epidemiologic data; 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.

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