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）健康登记处的数据显示，在倒塌后最初72小时内出现在归零地的第一反应者（FR）中心血管（CV）疾病增加。目前还没有确定WTC粉尘可以作为病原体改变CV健康。即使世贸中心粉尘不是FR中CV变化的直接诱导物，它们也可能在原位造成损害，从而调节另一种已知能够影响CV系统的共污染物的影响-并且在归零地空气中也以高水平存在-柴油废气颗粒（DEP;来自卡车，发电机，起重机）。我们之前的分析表明，大鼠暴露于碱性WTC粉尘[使用模拟FR口呼吸的暴露/水平]导致气道纤毛细胞数量和WTC粉尘本身的清除持续减少。因此，我们假设夹带的WTC粉尘可能作为CV损伤的直接诱导剂和/或由于该共污染物的肺滞留增加而引起增强的DEP诱导的CV损伤。作为FR模型，大鼠将连续暴露2天（2小时/天）。d，通过气管内吸入）对WTC粉尘（9/12和9/13现场采集）、DEP或两种污染物的组合，并检查其CV结构/功能的变化（后者包括心率[和变异性]、左心室每搏输出量、心输出量、射血分数和主动脉/肠系膜动脉血管收缩反应的离体测量）。暴露将使用通过“参考FR”从4小时内经历的粉尘/DEP水平外推得出的粉尘/DEP水平。提出了三个相互关联的具体目标：（1）首次确定暴露于WTC粉尘是否会导致CV结构/功能的变化：（2）确定WTC粉尘+ DEP联合暴露后CV的变化是否大于DEP单独暴露后CV的变化;和（3）证明与粉尘+ DEP共同暴露相关的CV变化的增加将部分地与DEP的肺滞留增加相关。这些在大鼠中进行的创新研究，使用相关的WTC粉尘，DEP和暴露情景，将使我们能够：澄清这些共污染物在最初72小时暴露的FR的CV健康变化中可能发挥的作用;获得这些FR中所见的CV问题增加的病因学的重要生化/分子线索;分析暴露于WTC粉尘对DEP保留的影响以及后者的后续毒性，因为它们与CV结构/功能的改变有关;作为补充目标，可能识别新的 血清标记物的心血管疾病诱导的变化，最终可用于确定更快的CV缺陷的存在，在仍然外表健康的暴露FR。研究解决的目标，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）;（战略目标1：减少消防员的CV死亡），并将与一项重大的研究实践（r2 p）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FR/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.