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：
8686840
负责人：
Gokhan M. Mutlu
金额：
$ 36.52万
依托单位：
UNIVERSITY OF 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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686840
关键词：
Accounting Acute Adenylate Cyclase Adrenergic Agonists Adrenergic Receptor Agonist Air Pollution Airborne Particulate Matter Alveolar Macrophages Animals Asthma Award Blood Pressure Breathing C-reactive protein CCL4 gene CREB1 gene Calcium Calcium Channel Cardiovascular system Catecholamines Cessation of life Chronic Obstructive Airway Disease Cities Coagulation Process Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Responsive DNA-Binding Protein Data Epinephrine Event Exposure to Fibrinogen Generations Genetic Hemostatic function Human Interleukin-6 JUN gene Life Expectancy Ligands Link Lung Lung Inflammation Mediating Mitochondria Mus Norepinephrine Particulate Matter Patients Pharmaceutical Preparations Plasminogen Play Production Prothrombin time assay Reactive Oxygen Species Reporting Risk Role Signal Transduction Sympathetic Nervous System Testing Thrombosis Tissues Transcription Factor AP-1 Tyrosine 3-Monooxygenase animal data autocrine clinically relevant exposed human population formoterol heart rate variability human data improved macrophage mortality novel p65 prevent response von Willebrand Factor years of life lost

项目摘要

DESCRIPTION (provided by applicant): Exposure to ambient particulate matter (PM) air pollution accounts up to 3.1 years of life lost in the most compared with the least polluted US cities. The mortality associated with acute exposure to ambient PM is largely due to ischemic cardiovascular events. While the mechanisms linking PM exposure with acute cardiovascular events are not fully understood, human and animal data increasingly suggest that PM-induced alterations in hemostasis resulting from lung inflammation and activation of the sympathetic nervous system play causal roles. In the first cycle of this award, we reported that acute exposure to PM causes lung macrophages to release interleukin-6 (IL-6), which accelerates arterial thrombosis in mice, a finding supported by human studies. In our preliminary data we observed that PM-induced opening of Calcium-Release Activated Calcium (CRAC) channels and mitochondrial reactive oxygen species (ROS) play a critical role in PM-induced IL-6 release. We also observed that mice exposed to inhaled PM had increased lung and systemic levels of epinephrine and norepinephrine, directly confirming data from human exposure studies suggesting that PM exposure activates the sympathetic nervous system. Surprisingly, the administration of a ¿-blocker or genetic loss of the ¿2-adrenergic receptor (¿2AR) inhibited the PM-induced release of IL-6 and the subsequent prothrombotic state. Conversely, inhalation of a long acting ¿2-agonist (formoterol) augmented the PM-induced release of IL-6 and the resulting prothrombotic state. These results suggest that activation of the sympathetic nervous system in response to PM augments the release of IL-6 from alveolar macrophages and contributes to resulting prothrombotic state. In the current proposal, we have developed 3 specific aims to test the hypothesis that stimulation of the ¿2AR by locally derived catecholamines augments the PM-induced release of IL-6 from alveolar macrophages and the resulting prothrombotic state through CRAC channel and ROS- mediated augmentation of cAMP production. In aim 1, we will determine whether the activation of alveolar macrophage ¿2ARs is required for the PM-induced release of IL-6 and the resulting prothrombotic state. In aim 2, we will determine whether PM-induced opening of CRAC channels and generation of mitochondrial ROS amplify the ¿2AR/cAMP-dependent augmentation of IL-6 release. In aim 3, we will determine whether autocrine catecholamine signaling in alveolar macrophages augments PM-induced IL-6 release and the resulting prothrombotic state. Our findings provide a novel mechanistic paradigm linking PM-induced lung inflammation and activation of the sympathetic nervous system with an increased risk of thrombosis leading to ischemic cardiovascular events. In addition, our observation that the administration of a widely used inhaled long acting ¿2AR agonist augments PM-induced IL-6 release and thrombosis provides a potential mechanism to explain the increasing body of evidence showing that the use of inhaled ¿2-agonists is associated with increased mortality in patients with COPD and asthma.

描述（由申请人提供）：与污染最轻的美国城市相比，暴露于环境颗粒物 (PM) 空气污染导致的生命损失高达 3.1 年与急性暴露于环境颗粒物 (PM) 相关的死亡主要是由于缺血所致。虽然 PM 暴露与急性心血管事件之间的联系机制尚不完全清楚，但人类和动物数据越来越多地表明，PM 引起的肺部炎症和交感神经系统激活引起的止血变化起着因果作用。在该奖项的第一个周期中，我们报告说，急性接触 PM 会导致肺巨噬细胞释放白细胞介素 6 (IL-6)，从而加速小鼠动脉血栓形成，这一发现得到了人类研究的支持，我们在初步数据中观察到 PM。诱导的钙释放激活钙 (CRAC) 通道和线粒体活性氧 (ROS) 的开放在 PM 诱导的 IL-6 释放中发挥着关键作用。我们还观察到，暴露于吸入 PM 的小鼠肺部和全身症状增加。肾上腺素和去甲肾上腺素的水平，直接证实了人体暴露研究的数据，表明 PM 暴露会激活交感神经系统。 -阻滞剂或基因丢失 ¿ 2-肾上腺素能受体 (¿2AR) 抑制 PM 诱导的 IL-6 释放以及随后的离线、吸入长效 ¿ 2-激动剂（福莫特罗）增强了 PM 诱导的 IL-6 释放以及由此产生的血栓前状态。这些结果表明，交感神经系统响应 PM 的激活增强了肺泡巨噬细胞的 IL-6 释放，并有助于产生血栓前状态。在当前的提议中，我们制定了 3 个具体目标来检验刺激 ¿局部衍生的儿茶酚胺的 2AR 增强了 PM 诱导的肺泡巨噬细胞中 IL-6 的释放，并通过 CRAC 通道和 ROS 介导的 cAMP 产生增强了血栓前状态。在目标 1 中，我们将确定肺泡巨噬细胞的激活是否有效。 2AR 是 PM 诱导的 IL-6 释放以及由此产生的促血栓状态所必需的。在目标 2 中，我们将确定 PM 诱导的 CRAC 通道开放和线粒体 ROS 的产生是否会放大 ¿ 2AR/cAMP 依赖性 IL-6 释放增强在目标 3 中，我们将确定肺泡巨噬细胞中的自分泌儿茶酚胺信号传导是否增强 PM 诱导的 IL-6 释放以及由此产生的促血栓状态，从而提供了一种将 PM- 联系起来的新机制范例。诱发肺部炎症和交感神经系统激活，增加血栓形成的风险，导致缺血性心血管事件。此外，我们观察到广泛使用的吸入长效药物的给药。 2AR 激动剂增强 PM 诱导的 IL-6 释放和血栓形成提供了一种潜在机制来解释越来越多的证据表明使用吸入 ¿ 2-激动剂与慢性阻塞性肺病和哮喘患者的死亡率增加有关。