在心力衰竭情况下可吸入颗粒污染物（PM2.5）介导的心肺毒理机制研究

Epidemiologic studies consistently demonstrate strong associations between the levels of ambient particulate matter (PM) air pollutants and cardiovascular mortality, hospital admissions, and emergency room visits. Acute and chronic cardiopulmonary toxicities of PM exposure in human and animal models include persistent lung inflammation, asthma exacerbation, heart rate alterations, myocardial ischemia, cardiac arrhythmias, and heart failure. Insights into the biologic mechanisms of PM-mediated cardiopulmonary toxicity remain limited, particularly the mechanisms underlying heart failure and arrhythmia exacerbations by PM. This application will address and compare the mechanistic effects of PM on cardiovascular responses in mice developing severe congestive heart failure (CHF) and arrhythmias. We hypothesize that PM-exacerbated cardiac arrhythmias involves multi-organ dysregulation (lung and heart) superimposed upon a susceptible, cardiac phenotype (heart failure) predisposed to develop PM-mediated exacerbated cardiac dysfunction. Direct PM-induced cardiopulmonary toxicity will be assessed by cell biologic, physiological, electrophysiological and toxicogenomic tools to elucidate the role of PM-induced pulmonary inflammation, endothelial integrity disruption, and cardiac ion channel dysregulation in cardiomyopathic aberrations. Specific Aim #1 will characterize mechanisms of PM-induced lung inflammation and disruption of vascular integrity contributing to PM-mediated cardiac toxicity. Specific Aim #2 will integrate the dysregulatory role of PM on cardiac ion channel expression and function as a terminal mechanism contributing to PM-mediated cardiac arrhythmias. In addition， with the expertise in toxicogenomics, we will define toxicogenomic molecular signature of different PM samples, which provide a novel tool for cardiopuomonary toxicity molecular prognosis. Together, utilizing multidisciplinary approaches, these studies will provide novel molecular mechanistic insights into PM-mediated cardiac arrhythmia generation and facilitate translation of this information into novel therapeutic strategies for patients at risk for adverse PM-induced cardiac outcomes.

近二十年的国内外流行病学研究证实，可吸入空气颗粒污染物（PM2.5）与心血管疾病的死亡率、入院率和急诊数量有很强的相关性。空气颗粒污染物在人类与动物模型中表现出急性和慢性心肺毒性，包括持久性肺部炎症反应、哮喘恶化、心肌缺血、心律失常、心力衰竭等。当前对PM2.5介导心肺毒性的生物机制研究仍然有限，特别是有关其对已有心力衰竭的病人和小鼠模型的毒理研究几乎还是空白。本课题组拟在已建立多年的PM2.5毒理研究基础上，针对PM2.5对充血性心力衰竭小鼠心肺毒理作用，尤其是其在肺部血管完整性和肺部损伤，以及心律失常发生、发展中的作用机制进行深入研究，以逐步阐明PM2.5在心衰条件下的高敏感毒性的分子机制。在此基础上，利用毒理基因组学的方法，建立不同PM2.5的心肺毒理分子指纹,构建PM2.5心肺毒性基因组水平的分子检测工具，有助于转化形成针对PM2.5在高危患者中导致不良反应的治疗和和检测的工具。

近二十年的国际国内流行病学研究发现了空气颗粒污染物和心血管死亡率、 住院治疗和急诊量很强的相关性。空气颗粒污染物（PM）在人类与动物模型中表现出急性和慢性心肺毒性，包括持久性肺部炎症反应、哮喘恶化、心率变化、心肌缺血、心律失常、心力衰竭。当前对空气颗粒污染物介导心肺毒性的生物机制研究仍然有限，特别是对已有心力衰竭的病人和小鼠模型，这方面的研究还是空白。此面上项目将研究空气颗粒对充血性心力衰竭小鼠心肺毒理，尤其是肺血管完整性，肺损伤，和心律失常的研究。目标一将深入研究的空气颗粒对肺炎症和血管的完整性破坏的机制；目标一将探讨空气颗粒对心脏离子通道的表达和功能的毒理作用，作为终端机制去了解空气颗粒介导的心律失常。在此基础上，我们利用毒理基因组学的方法，建立不同空气颗粒的心肺毒理分子指纹,从而在国内首次建立空气颗粒污染物的心肺毒性基因组水平的分子检测工具。在一起，运用多种研究，此项目将提供空气颗粒污染物介导的心肺毒性的新的分子机制，并有助于转化新型的针对空气颗粒在高危患者中导致不良反应的治疗和检测策略。