WTC Dust Size and Alkalinity as Factors in First Responder Chronic Lung Ailments

描述（由申请人提供）：世贸中心倒塌后的第一个72小时内，第一反应者出现在世贸中心遗址，他们的呼吸系统健康受到了严重损害。这包括慢性疾病，如结节样肉芽肿性肺病（SLGPD）和持续气道高反应性（AHR;慢性哮喘的定义特征）。虽然已经进行了一些使用建筑物来源的WTC粉尘的动物研究，以更好地了解一些响应者疾病的病因，但他们主要使用可能沉积在肺部的粉尘部分（细，直径2.5 5 m [da]），2001年9月13日之后收集的粉尘，或不反映大多数响应者经历的暴露场景的方案。由于在第一反应者的肺中发现了显著的粗WTC尘埃颗粒沉积，并且WTC颗粒的碱度随着da增加，我们假设：（1）大颗粒的存在增加，肺内碱性颗粒> 2.55m者，SLGPD和AHR的发生率和严重程度较高;和（2）这两种疾病的潜在机制是（A）大颗粒的碱性最初损害肺上皮，从而触发与持续AHR相关的气道重塑并降低颗粒清除率，和（B）与现在保留的WTC颗粒相关的金属产生多种毒性，包括肉芽肿诱导和促进进行中的气道重塑。作为第一反应者的模型，大鼠将连续3天（4小时/天，通过气管内吸入）暴露于WTC粉尘（2001年9月12日至13日采集），并在暴露后1年内进行检查。所有使用的粉尘浓度将从9/11-13/01在归零地出现的粉尘浓度外推。提出了四个相互关联的具体目标，以证明：（1）大量增加（2）粉尘中碱性成分的存在对AHR和SLGPD的发病率和严重程度有重要影响;（3）粉尘暴露后气道高反应的发生率和严重程度取决于气道上皮细胞的早期损伤和随后促重塑因子的释放;（4）接尘后SLGPD（和AHR）的发生率和严重程度与粉尘滞留量的改变有关。这些使用动物模型、相关WTC粉尘和相关暴露情景的研究将澄清9/11-13/01期间吸入的WTC粉尘可能对应答者呼吸系统健康变化的作用，为报告的慢性肺部疾病的病因提供重要线索，并允许监测暴露于完整的WTC粉尘（或其大尺寸部分）对AHR和SLGPD的开始\进展的影响。这里获得的数据将提供有价值的信息之间的关系的物理化学性质的建筑物倒塌/拆除相关的粉尘和肺中的毒理学效应。希望工人安全\应急计划和呼吸医学的适当调查人员将使用这些信息分别制定前瞻性行动计划和重点治疗，以保护未来建筑物倒塌时消防员/救援人员的呼吸健康。 公共卫生相关性：拟议的研究旨在更好地了解9/11首次应答者中两种慢性肺部疾病（AHR和SLGPD）的发病率和严重程度增加的基础。这些使用动物模型、相关WTC粉尘和相关暴露情景的研究将：允许澄清在9/11-9/13/01期间吸入的WTC粉尘在应答者呼吸系统健康变化中可能发挥的作用;提供有关这些持续慢性肺部疾病的病因的重要线索;并且，允许监测暴露于完整的WTC粉尘（或其大尺寸部分）对AHR和SLGPD的开始/进展的影响。此处获得的数据将提供有关建筑物倒塌/拆除相关粉尘的物理化学性质与肺部毒理学效应之间关系的有价值信息，工人安全\应急计划和呼吸医学中的适当调查人员可以使用这些信息分别制定前瞻性行动计划和重点治疗，以保护消防员，救援人员，以及其他可能会被召唤来应对未来任何建筑物倒塌的人。

DESCRIPTION (provided by applicant): First Responders present at Ground Zero during the first 72 hr after the WTC collapse have suffered significant damage to their respiratory health. This includes chronic disorders like sarcoid-like granulomatous pulmonary disease (SLGPD) and persistent airway hyperreactivity (AHR; defining feature of chronic asthma). While a number of animal studies using building-derived WTC dusts have been performed to better understand the etiology of some Responder ailments, they primarily used only a dust fraction (fine, d 2.5 5m diameter [da]) likely to be deposited in the lung, dusts collected after 9/13/01, or regimens that did not reflect exposure scenarios most Responders underwent. As significant coarse WTC dust particle deposition was found in the lungs of First Responders, and the alkalinity of WTC particles increases with da, we hypothesize that: (1) an increased presence of large (>2.5 5m) alkaline particles in their lungs contributed to the high incidence\severity of SLGPD and AHR; and, (2) a mechanism underlying these two disorders is that (A) the alkalinity of the large particles initially damaged the lung epithelium so that airway remodeling associated with persistent AHR was triggered and particle clearance was reduced, and (B) metals associated with the now-retained WTC particles exerted a variety of toxicities including granuloma induction and promotion of ongoing airway remodeling. As models for First Responders, rats will be exposed on 3 consecutive days (4 hr/d, via intratracheal inhalation) to WTC dusts (collected 9/12-13/01) and examined over a 1-yr post-exposure period. All dust concentrations used will be extrapolated from those present at Ground Zero on 9/11-13/01. Four interrelated Specific Aims are proposed to demonstrate that the: (1) increases in amounts of large (>2.5 5m) WTC particles in the lungs contribute to increases in AHR and SLGPD incidence\severity; (2) presence of alkaline portions of WTC dusts is critical to the observed AHR and SLGPD incidence\severity; (3) AHR incidence\severity after WTC dust exposure depends on initial airway epithelium damage and subsequent release of factors to promote remodeling; and, (4) SLGPD (and AHR) incidence\severity after WTC dust exposure is related to altered dust retention. These studies using an animal model, relevant WTC dusts, and relevant exposure scenarios will permit clarification of what role those WTC dusts inhaled during 9/11-13/01 may have had in the changes in Responders' respiratory health, provide important clues as to the etiology of the reported chronic lung disorders, and allow monitoring of effects from exposure to intact WTC dusts (or its large size fractions) on the initiation\progression of AHR and SLGPD. Data obtained here will provide valuable information about relation- ships between the physicochemical properties of building collapse-/demolition-associated dusts and toxicologic effects in the lungs. It is hoped that appropriate Investigators in Worker Safety\Emergency Planning and in Respiratory Medicine will then use this information to develop, respectively, prospective action plans and focused treatments to protect the respiratory health of firefighters/rescuers called to future building collapses. Public Health Relevance: The proposed studies seek to gain a better understanding of the bases for the increasing incidence and severity of two chronic lung disorders, AHR and SLGPD, in 9/11 First Responders. These studies which use an animal model, relevant WTC dusts, and relevant exposure scenarios will: permit clarification of what role those WTC dusts inhaled during 9/11-9/13/01 may have had in the changes in the Responders' respiratory health; provide important clues as to the etiology of some of these ongoing chronic lung disorders; and, allow monitor- ing of effects from exposure to intact WTC dusts (or its large size fractions) on the initiation\progression of AHR and SLGPD. Data obtained here will provide valuable information concerning relationships between physico- chemical properties of building collapse-/demolition-associated dusts and toxicologic effects in the lungs that appropriate Investigators in Worker Safety\Emergency Planning and in Respiratory Medicine could use to develop, respectively, prospective action plans and focused treatments to protect the respiratory health of firefighters, rescue personnel, and others who may likely be called to any future building collapse.