Effects of WTC Dust Exposure on Cardiac and Cognitive Functions

摘要/摘要 数据显示急救者心血管(CVD)和神经退行性疾病的增加 (FR)在9/11-13/01期间出现在世贸中心遗址的人。虽然它还没有显示出WTC (世界贸易中心)粉尘是FR这些病理的原因，我们对暴露于WTC的SHR大鼠进行的研究 粉尘[在模拟口呼吸FR的范例中]注意到心血管功能和心脏缝隙的显著变化 连接蛋白表达和超微结构重塑，就像心力衰竭一样。这些老鼠也有 持续(长达1年的暴露后)呼吸道纤毛细胞减少和肺部粉尘清除。它是 因此，与其他城市相比，暴露在WTC粉尘中可能导致现场反应夸大 空气污染物，包括颗粒物(PM)。我们知道长期暴露在环境颗粒物中会导致心脏 小鼠的衰竭表型(心功能下降和细胞功能受损)和神经学以及 阿尔茨海默病(AD)样变化(BACE蛋白、APP处理和Aβ[淀粉样蛋白-β]水平增加) 在他们的大脑里。由于心血管疾病和阿尔茨海默病都与年龄有关，具有共同的危险因素，具有重叠的生化特征，以及 以淀粉样前体蛋白聚集体(在AD大脑和CVD心脏中发现)为特征，基于 “心与头”的致病模式，我们假设吸入地面零度尘埃颗粒 可能会导致--在某种程度上夸大了PM引起的--心脏和认知功能的改变，因此 对FR的健康造成严重的慢性影响。作为模型，SHR大鼠将暴露于WTC粉尘(使用 目前WTC项目中的范例：连续2天，每天2小时，气管内吸入，使用收集的粉尘 现场9/12-13/01)。无论是纵向还是在暴露后1年的固定时间点，数据都将 为了支持两个相互关联的目标而获得的。目标1将确定WTC粉尘暴露对心血管功能的影响 而Aβ则聚集在心中积聚。目标2将评估暴露对发育的影响 神经退行性疾病。我们知道，到目前为止，AD和FR暴露之间还没有记录在案的联系 在世贸中心遗址。然而，与人们期待已久的肺癌风险增加一样，人们不能直接 排除了仅仅由于缺乏流行病学数据而导致这种特殊病理发展的可能性- 约会。因此，在补充目标中，暴露的大鼠将接受额外的认知研究和大脑 将检测神经肽-Y和N-乙酰天冬氨酸的水平，看看是否有诱导的变化。 时间反映了创伤后应激障碍，这是暴露在FR中的一个有很好记录的结果。这些研究将允许我们，对于 第一次，确定任何WTC粉尘引起的心血管功能障碍的发病/进展的时间进程和 暴露于宿主的神经退行性疾病。这些研究涉及NIOSH目标(CVD跨部门 方案、公共安全方案[优先事项1：减少消防员的慢性病]和FFFFIPP[目标1： 减少消防员中的CV死亡])，保持主要的R2P倡议，以减少消防员/FR中的疾病 通过NIOSH产生的知识、干预、技术，并完成Zadroga法案的研究任务。

SUMMARY/ABSTRACT Data have revealed increases in cardiovascular (CVD) and neurodegenerative diseases in First Responders (FR) who were present at the Ground Zero over the 9/11-13/01 period. While it has yet not been shown if WTC (World Trade Center) dusts were causative for these pathologies in FR, our study of SHR rats exposed to WTC dusts [in paradigms mimicking mouthbreathing FR] noted significantly changes in CV function and cardiac gap junction protein expression, and ultrastructural remodeling like that seen in heart failure. These rats also had persistent (up to 1 yr post-exposure) reductions in airway ciliated cells and dust clearance from the lung. It is thus likely exposures to WTC dusts resulted in exaggerated responses in situ compared to that by other urban air pollutants, including particulate matter (PM). We know long-term exposure to ambient PM caused a heart failure phenotype in mice (decreased cardiac function and impaired cell function) and neurologic as well as Alzheimer disease (AD)-like changes (increased levels of BACE protein, APP processing, and Aβ [amyloid-β]) in their brains. As both CVD and AD are age-related, share risk-factors, have overlapping bio-chemistries, and are characterized by aggregates of amyloid precursor protein (found in AD brains and CVD hearts), based on the “heart-to-head” pathogenesis paradigm, we hypothesize here that inhalation of Ground Zero dust particles likely led - in a manner exaggerating that caused by PM - to alterations in cardiac and cognitive function, so as to impart severe chronic impacts on FR health. As models, SHR rats will be exposed to WTC dust (using paradigms as in current WTC project: 2 consecutive days, 2 hr/d, intratracheal inhalation, using dusts collected on-site 9/12-13/01). Both longitudinally and at fixed timepoints over a 1-yr post-exposure period, data will be obtained in support of two inter-related Aims. Aim 1 will define effects of WTC dust exposures on CV function and Aβ aggregate accumulation in the heart. Aim 2 will assess effects of the exposures on development of neurodegenerative disease. We are aware there is as-yet no documented link between AD and FR exposures at Ground Zero. However, as with the long-expected increased risk for lung cancer, one cannot outright preclude a possibility of this specific pathology developing simply due to absence of epidemiologic data to- date. Accordingly, in a Supplemental Aim, exposed rats will undergo additional cognitive studies and brain levels of Neuropeptide-Y and N-acetylaspartate will be examined to see if there were changes induced over time reflective of PTSD, an well-documented outcome among exposed FR. The studies will allow us, for the first time, to determine the time-course of any WTC dust-induced onset/progression of CV dysfunction and neurodegenerative disorders in exposed hosts. The studies address NIOSH goals (CVD Cross-Sector Program, Public Safety Program [Priority 1: Reduce chronic illnesses among firefighters] and FFFFIPP [Goal 1: Reduce CV deaths among firefighters]), keep with major r2p initiatives to reduce illness among firefighters/FR via NIOSH-generated knowledge, interventions, technologies, and fulfill the Zadroga Act research mandate.