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

描述(由申请人提供)：在世贸中心倒塌后的72小时内，在世贸中心倒塌后的第一个72小时内，在世贸中心遗址出现的第一批应答者的呼吸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部疾病(SLGPD)和持续性呼吸道高反应性(AHR；慢性哮喘的定义特征)。虽然使用来自建筑的WTC粉尘进行了一些动物研究，以更好地了解某些响应者疾病的病因，但他们主要只使用了可能沉积在肺部的粉尘部分(细，d 2.5 5米直径[da])，在9/13/01之后收集的粉尘，或没有反映大多数响应者经历的暴露情景的方案。由于第一反应者肺中有明显的粗WTC尘粒沉积，且WTC粒子的碱度随da的增加而增加，我们推测：(1)大的(-gt；2.5~5m)碱性粒子在他们的肺中增加是SLGPD和AHR的高发病率和严重程度；(2)这两种疾病的潜在机制是：(A)大颗粒的碱度最初损害了肺上皮细胞，从而触发了与持续性AHR相关的气道重塑，并降低了颗粒清除量，以及(B)与现保留的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First Responder的模型，大鼠将连续3天(4小时/d，通过气管内吸入)暴露于WTC粉尘(收集于2001年9月12日至13日)，并在暴露后1年内进行检查。所有使用的尘埃浓度将根据9/11-13/01年9/11-13在世贸中心遗址的浓度进行推断。提出了四个相互关联的具体目标，以证明：(1)肺中大的(-gt；2.5，5m)WTC颗粒数量的增加有助于AHR和SLGPD发生率/严重性的增加；(2)WTC粉尘中碱性部分的存在对观察到的AHR和SLGPD的发生率/严重性是关键的；(3)WTC粉尘暴露后的AHR发生率/严重性取决于最初的呼吸道上皮损伤和随后促进重塑的因子的释放；以及(4)WTC粉尘暴露后SLGPD(和AHR)的发生率/严重性与改变的粉尘滞留有关。这些使用动物模型、相关WTC粉尘和相关暴露情景的研究将有助于澄清这些WTC粉尘在9/11-13/01期间吸入的WTC粉尘在应答者的呼吸健康变化中可能起到的作用，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WTC粉尘(或其大尺寸部分)对AHR和SLGPD发生和发展的影响。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性质与肺部毒理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前瞻性行动计划和重点治疗，以保护被召唤到未来建筑物倒塌的消防员/救援人员的呼吸健康。 公共卫生相关性：拟议的研究试图更好地了解9/11 First Responder中AHR和SLGPD这两种慢性肺部疾病发病率和严重性增加的基础。这些研究使用动物模型、相关的WTC粉尘和相关的暴露情景，将：澄清这些WTC粉尘在9/11-9/13/01期间吸入的WTC粉尘可能在应答者的呼吸健康变化中所起的作用；为这些持续的慢性肺部疾病的一些病因提供重要线索；以及，允许监测暴露于完整的WTC粉尘(或其大尺寸组分)对AHR和SLGPD发生和发展的影响。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性质与肺部毒理效应之间关系的宝贵信息，工人安全/应急计划和呼吸医学的适当调查人员可以利用这些信息分别制定前瞻性行动计划和重点治疗方案，以保护消防员、救援人员和其他可能因未来建筑物倒塌而被召唤的人的呼吸健康。

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.