Roles for WTC Dust and DEP Co-pollutant in First Responder Cardiovascular Ailments

 描述(由申请人提供)：来自临床研究和世界贸易中心(WTC)健康注册中心的数据显示，在最初的72小时内，在世贸中心遗址现场的急救人员(FR)中，心血管疾病(CV)的发病率有所增加。在崩塌之后。目前还没有确定WTC粉尘是否可以作为改变心血管健康的致病因素。即使WTC粉尘不是直接导致FR中CV变化的诱因，它们也有可能在现场造成损害，影响另一种已知能够影响CV系统的共污染物的影响--而且在归零地空气-柴油废气中也存在高水平的颗粒物(DEP；来自卡车、发电机、起重机)。我们之前的分析表明，暴露于碱性WTC粉尘[使用模拟FR口呼吸的暴露/水平]的大鼠导致呼吸道纤毛细胞数量和WTC粉尘本身的清除持续减少。因此，我们推测，携带的WTC粉尘可能是肺循环损伤的直接诱因，和/或由于这种共同污染物在肺内滞留的增加而导致DEP引起的肺循环损伤增加。作为FR模型，大鼠将连续2天(2小时/d，气管内吸入)暴露于WTC粉尘(现场收集的9/12和9/13)、DEP或这两种污染物的组合中，并在此后的多个时间点检查其心血管结构/功能的变化(后者包括心率[和变异性]、左心室每搏量、心输出量、射血分数和体外测量的主动脉/肠系膜动脉血管收缩反应)。曝光量将使用通过“参考FR”从4小时内经历的尘埃/DEP水平推算出来的水平。提出了三个相互关联的具体目标：(1)首次确定接触WTC粉尘是否会导致心血管结构/功能的变化：(2)确定WTC粉尘+DEP联合暴露后的CV变化是否会比单独接触DEP后更大；以及(3)证明与粉尘+DEP联合暴露相关的CV变化的增加将部分与DEP的肺滞留增加有关。这些针对大鼠的创新性研究，使用相关的WTC粉尘、DEP和暴露情景，将使我们能够：澄清这些共同污染物可能在最初72小时暴露的FR的心血管健康中所见的变化中起到什么作用；获得重要的生化/分子线索，找出这些FR中出现的日益严重的心血管问题的病因；分析暴露于WTC粉尘对DEP保留的影响以及随后与心血管结构/功能改变有关的后者的毒性；以及，作为补充目标，潜在地识别新的 暴露诱导的CV变化的血清标记物，最终可用于在仍然外表健康的暴露FR中更早地识别CV缺陷的存在。这些研究涉及NIOSH：心血管疾病跨部门计划、公共安全计划(优先事项1：减少消防员中的慢性病)和FFFFIPP(战略目标1：减少消防员中的心血管死亡)的目标，并将与一项重大的研究实践(R2P)倡议保持一致，即通过NIOSH产生的知识、干预措施和技术帮助减少消防员/消防员的疾病。

 DESCRIPTION (provided by applicant): Data from clinical studies and the World Trade Center (WTC) Health Registry have revealed increases in cardiovascular (CV) diseases among first responders (FR) who were present at Ground Zero over the initial 72 hr. after the collapse. It has yet not been established that WTC dusts can act as causative agents to alter CV health. Even if WTC dusts were not direct inducers of CV changes in the FR, it was possible they might have caused damage in situ that modulated the impact of another co-pollutant with a known ability to impact the CV system - and was also present at high levels in Ground Zero air - diesel exhaust particles (DEP; from trucks, generators, cranes). Our previous analyses showed that rats exposed to the alkaline WTC dusts [using exposures/levels mimicking FR mouth-breathing] led to persistent reductions in airway ciliated cell numbers and clearance of the WTC dust itself. Accordingly, we hypothesize that entrained WTC dusts may have acted as direct inducers of CV damage and/or caused enhanced DEP-induced CV injuries as a result of increased pulmonary retention of this co-pollutant. As FR models, rats will be exposed on 2 consecutive days (2 hr./d, by intratracheal inhalation) to WTC dust (collected on-site 9/12 & 9/13), DEP, or the two pollutants in combination, and examined for changes in their CV structures/functions (latter to include heart rate [and variability], left ventricular stroke volume, cardiac output, ejection fraction, and ex vivo measures of aorta/mesenteric artery vasoconstrictor responses) at multiple timepoints over 1 yr thereafter. Exposures will use dust/DEP levels extrapolated from those experienced over 4-hr periods by `reference FR'. Three inter-related Specific Aims are proposed to: (1) determine for first time if changes in CV structure/function occur as a result of exposure to WTC dusts: (2) ascertain if CV changes will be greater after WTC dust + DEP co-exposures relative to that due to DEP alone; and, (3) demonstrate that increases in CV changes associated with dust + DEP co-exposures will be related, in part, to increased lung retention of DEP. These innovative studies in rats, using relevant WTC dusts, DEP, and exposure scenarios, will allow us to: clarify what role these co-pollutants may have had in changes seen in the CV health of FR exposed in that initial 72 hr; obtain important biochemical/molecular clues to etiologies for the increasing CV problems seen in these FR; analyze the impact from exposure to WTC dusts on DEP retention and subsequent toxicities from the latter as they pertain to altered CV structures/functions; and, as a supplemental goal, potentially identify novel sero-markers of exposure-induced CV changes that could ultimately be used to identify sooner a presence of CV defects in still-outwardly healthy exposed FR. The studies address goals of the NIOSH: Cardiovascular Disease Cross-Sector Program, Public Safety Program (Priority 1: Reduce chronic illnesses among firefighters); and, FFFFIPP (Strategic Goal 1: Reduce CV deaths among firefighters), and will be in keeping with a major Research to Practice (r2p) initiative, i.e., to help reduce illness among FR/firefighters via NIOSH-generated knowledge, interventions, technologies.