Mechanisms of airborne particulate matter induced thrombosis

空气颗粒物诱发血栓形成的机制

• 批准号: 8916719
• 负责人: Gokhan M. Mutlu
• 金额: $ 35.44万
• 依托单位: UNIVERSITY OF 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916719
• 关键词: Accounting; Acute; Adenylate Cyclase; Adrenergic Agonists; Adrenergic Receptor; Agonist; Air Pollution; Airborne Particulate Matter; Alveolar Macrophages; Animals; Asthma; Award; 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; blood pressure reduction; 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，令人惊讶的是，使用 β-阻滞剂或 β2-肾上腺素受体 (β2AR) 基因缺失会抑制 PM-。诱导的 IL-6 释放和随后的离线状态，吸入长效β2-激动剂（福莫特罗）增强了 PM 诱导的 IL-6 和这些结果表明，交感神经系统对 PM 的反应会增加肺泡巨噬细胞释放 IL-6，并有助于产生血栓前状态。在当前的提议中，我们制定了 3 个具体目标来测试。假设局部衍生的儿茶酚胺刺激 2AR 会增强 PM 诱导的肺泡巨噬细胞释放 IL-6，并通过 CRAC 通道和 ROS 介导的增强而产生血栓前状态在目标 1 中，我们将确定肺泡巨噬细胞 2AR 的激活是否是 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 是否诱导 IL-6 的开放。 CRAC 通道和线粒体 ROS 的产生放大了 IL-6 释放的 2AR/cAMP 依赖性增强。在目标 3 中，我们将确定肺泡巨噬细胞中是否存在自分泌儿茶酚胺信号传导。增加 PM 诱导的 IL-6 释放以及由此产生的血栓前状态，提供了一种新的机制范式，将 PM 诱导的肺部炎症和交感神经系统的激活与导致缺血性心血管事件的血栓形成风险增加联系起来。观察到，广泛使用的吸入长效 β2-AR 激动剂的施用会增加 PM 诱导的 IL-6 释放和血栓形成，这提供了一个潜在的机制来解释越来越多的证据表明，使用吸入式 β2-激动剂与 COPD 和哮喘患者死亡率增加有关。