Mechanisms of Particulate Matter Induced Death

颗粒物诱发死亡的机制

• 批准号: 7102957
• 负责人: GR Scott Budinger
• 金额: $ 33.67万
• 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: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102957
• 关键词: BCL2 gene /protein; JUN kinase; air pollution; apoptosis; biological signal transduction; electron microscopy; environmental exposure; free radical oxygen; genetically modified animals; green fluorescent proteins; iron; laboratory mouse; lung injury; mitochondria; mitogen activated protein kinase; molecular genetics; p53 gene /protein; particle; pathologic process; polymerase chain reaction; respiratory epithelium; terminal nick end labeling; tumor suppressor genes; BCL2 gene /protein; JUN kinase; air pollution; apoptosis; biological signal transduction; electron microscopy; environmental exposure; free radical oxygen; genetically modified animals; green fluorescent proteins; iron; laboratory mouse; lung injury; mitochondria; mitogen activated protein kinase; molecular genetics; p53 gene /protein; particle; pathologic process; polymerase chain reaction; respiratory epithelium; terminal nick end labeling; tumor suppressor genes

DESCRIPTION (provided by applicant): Ambient particulate matter (PM) is increasingly recognized as a significant contributor to human cardiopulmonary morbidity and mortality both in the United States and worldwide. There are strong epidemiologic data that link the daily levels of ambient PM to pulmonary symptoms, rates of infections, school absenteeism, daily use of specific medications, hospitalizations for cardiopulmonary disease, and daily cardiopulmonary mortality rates. Longer term exposure to ambient particulate matter has been associated with an increase in the prevalence of obstructive lung disease and the development of lung cancer. While relatively little is known about the mechanisms by which particulate matter induces disease, it is hypothesized that exposure of epithelial lining cells to ambient particulate matter within the respiratory tract results in the development of reactive oxygen species (ROS) that in turn induce injury and inflammation. We have observed that exposure to well-characterized particulate matter collected from ambient air in Dusseldorf, Germany and Washington, D.C. results in death of alveolar epithelial cells through a mechanism that appears to require iron and the mitochondrial generation of ROS. In this proposal, we seek to determine the mechanisms that underlie the generation of reactive oxygen species in response to exposure to particulate matter and the signaling pathways evoked that link the generation of ROS to alveolar epithelial cell death. Specifically, we seek to determine (1) whether iron and ROS generated from the mitochondria are required for particulate matter induced lung epithelial cell death in vitro and in vivo; (2) whether iron and ROS generated in response to particulate matter cause an apoptosis signal-regulating kinase 1 (ASK1) dependent activation of JNK and p38 to induce lung epithelial cell death and (3) whether the activation of p53 acts through the pro-apoptotic Bcl-2 protein PUMA to induce lung epithelial cell death following exposure to particulate matter. These studies combine molecular-genetic approaches to examine the mechanisms of particulate matter induced cell death in vitro and in vivo. Recent estimates suggest that the average loss of life expectancy related to chronic air pollution exposure is between 1.8 and 3.1 years for individuals living in the most polluted American cities. Understanding the mechanisms by which particulate matter induces injury in the lung will help us better design pollution control and response measures that will have a major impact on public health.

描述（由申请人提供）：在美国和全球范围内，环境颗粒物（PM）越来越被认为是人类心肺发病率和死亡率的重要原因。有强大的流行病学数据将周围PM的每日水平与肺部症状，感染率，学校缺勤率，日常使用特定药物，心肺疾病住院治疗以及每日心肺死亡率联系起来。长期暴露于环境颗粒物与阻塞性肺部疾病患病率的增加和肺癌发展有关。虽然对颗粒物诱导疾病的机制知之甚少，但假设上皮衬细胞暴露于呼吸道内的环境颗粒物物质会导致反应性氧（ROS）的发展，从而导致损伤和炎症。我们已经观察到，从杜塞尔多夫，德国和华盛顿特区的环境空气中收集的特征良好的颗粒物的暴露导致肺泡上皮细胞死亡，该机制似乎需要铁和线粒体生成ROS。在此提案中，我们试图确定响应于暴露于颗粒物质的反应性氧的生成的机制，以及唤起的信号通路将ROS的产生与肺泡上皮细胞死亡联系起来。具体而言，我们试图确定（1）颗粒物诱导的肺上皮细胞死亡在体外和体内是否需要从线粒体产生的铁和ROS； （2）对颗粒物的响应产生的铁和ROS是否导致凋亡信号调节激酶1（ASK1）JNK和p38的依赖激活诱导肺上皮细胞死亡以及（3）p53的激活是否通过促进性BCL-2蛋白质PUMA起作用，以诱导肺部上皮细胞死亡，以诱发型疾病的曝光问题。这些研究结合了分子遗传学方法，以检查颗粒物质诱导的细胞死亡的体外和体内的机制。最近的估计表明，生活在美国污染最严重的城市中，与慢性空气污染暴露有关的平均预期寿命损失在1.8至3。1年之间。了解颗粒物在肺中诱导损伤的机制将有助于我们更好地设计污染控制和对公共卫生产生重大影响的污染措施。