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72小时内出现在世贸中心遗址的第一响应者的呼吸系统健康受到严重损害。这包括慢性疾病，如结节样肉芽肿性肺病（SLGPD）和持续性气道高反应性（AHR，慢性哮喘的定义特征）。为了更好地了解一些响应者疾病的病因，已经进行了一些使用建筑物产生的WTC粉尘的动物研究，但它们主要只使用可能沉积在肺部的粉尘部分（细，直径2.5 m [d]）， 2001年9月13日之后收集的粉尘，或者不反映大多数响应者所经历的暴露情景的方案。由于第一响应者肺部存在显著的粗质WTC粉尘颗粒沉积，且WTC颗粒的碱度随时间的增加而增加，我们假设：(1)肺中较大（>2.5 m）碱性颗粒的增加与SLGPD和AHR的高发病率和严重程度有关；(2)这两种疾病的机制是：(a)大颗粒的碱度最初损害了肺上皮，从而触发了与持续性AHR相关的气道重塑，颗粒清除减少；(B)与现在保留的WTC颗粒相关的金属施加了各种毒性，包括诱导肉芽肿和促进正在进行的气道重塑。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）暴露于世贸中心粉尘（收集于9/12-13/01），并在暴露后1年进行检查。所有使用的粉尘浓度都是根据9/11-13/01世贸中心的粉尘浓度推断出来的。提出了四个相互关联的特定目的，以证明：(1)肺中大颗粒（>2.5 m） WTC颗粒数量的增加有助于AHR和SLGPD发病率的增加；(2) WTC粉尘碱性部分的存在对观测到的AHR和SLGPD发病率的严重程度至关重要；(3) WTC粉尘暴露后AHR的发生率和严重程度取决于初始气道上皮损伤和随后促进重塑的因子释放；(4) WTC粉尘暴露后SLGPD（和AHR）发生率/严重程度与粉尘滞留改变有关。这些研究使用了动物模型、相关的WTC粉尘和相关的暴露情景，将有助于澄清9/11-13/01期间吸入的WTC粉尘在应答者呼吸健康变化中的作用，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（或其大颗粒）对AHR和SLGPD的发生和进展的影响。这里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特性与肺部毒理学效应之间关系的宝贵信息。希望工人安全/应急计划和呼吸医学的适当调查人员随后将利用这些信息分别制定预期行动计划和重点治疗方法，以保护未来建筑物倒塌时被叫到的消防员/救援人员的呼吸健康。

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.