Mechanisms of airborne particulate matter induced thrombosis

空气颗粒物诱发血栓形成的机制

• 批准号: 8545847
• 负责人: Gokhan M. Mutlu
• 金额: $ 34.07万
• 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 2014-05-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545847
• 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; 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

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（由适用提供）：与美国城市最少的城市相比，接触周围特定问题（PM）空气污染账户最多3.1年。与急性暴露于环境PM有关的死亡率主要是由于缺血性心血管事件。尽管尚未完全了解将PM暴露与急性心血管事件联系起来的机制，但人类和动物数据越来越多地表明，PM诱导的肺部感染引起的止血和交感神经系统激活引起的止血变化。在该奖项的第一个周期中，我们报告说，急性暴露于PM会导致肺巨噬细胞释放白介素-6（IL-6），该发现加速了小鼠的动脉血栓形成，这一发现得到了人类研究的支持。在我们的初步数据中，我们观察到，PM诱导的钙释钙激活钙（CRAC）通道和线粒体活性氧（ROS）在PM诱导的IL-6释放中起着至关重要的作用。我们还观察到，暴露于Incorpated PM的小鼠的肺和去甲肾上腺素的肺和全身水平升高，直接证实了人类暴露研究的数据，这表明PM暴露会激活交感神经系统。令人惊讶的是，2-肾上腺素能受体（2AR）的施用或遗传丧失抑制了PM诱导的IL-6释放和随后的促血栓形成状态。相反，吸入长作用的2个激动剂（Formoterol）增强了PM诱导的IL-6的释放和由此产生的实现血栓形成态。这些结果表明，响应PM的交感神经系统的激活增强了从肺泡巨噬细胞中释放IL-6，并导致产生的血栓性状态。在当前的提案中，我们开发了3种特定的目的，以测试以下假设：通过局部衍生的儿茶酚胺刺激2AR，增强了PM诱导的IL-6从肺泡巨噬细胞中释放出来，以及通过CRAC通道和CRAC通道和ROS介导的营地生产增强的产生的实现性态。在AIM 1中，我们将确定肺泡巨噬细胞的激活是否需要PM诱导的IL-6释放和由此产生的促血栓形成状态。在AIM 2中，我们将确定PM诱导的CRAC通道的打开和线粒体ROS的产生是否会扩大IL-6释放的2AR/CAMP依赖性增强。在AIM 3中，我们将确定Alloolar巨噬细胞中的自分泌儿茶酚胺信号传导是否会增加PM诱导的IL-6释放和由此产生的促血栓性状态。我们的发现提供了一种新型的机械范式，将PM诱导的肺部感染和交感神经系统激活与血栓形成的风险增加，导致缺血性心血管事件。此外，我们的观察是，对广泛使用的遗传长作用2AR激动剂的给药增强了PM诱导的IL-6释放和血栓形成提供了一种潜在的机制，可以解释越来越多的证据，表明使用遗传的2-激动剂与COPD患者患者的死亡率增加有关。