Advancing Non-Invasive Diagnostics and Treatments of Deployment-Related Chronic Lung Disease in Gulf War Veterans

基本原理。海湾战争退伍军人的呼吸系统疾病发病率增加 (GW)[和9/11之后的冲突。考虑到大量潜在的呼吸道暴露，怀疑是吸入性损伤。 毒素。2011年的一项里程碑式的研究(1)描述了一群9/11事件后的士兵患有不明原因的呼吸困难和 接受外科肺活检的运动耐量受损；发现有证据表明慢性 增厚的纤维细支气管炎称为部署相关性慢性毛细支气管炎 (DR-CB)。我们进行了初步分析，以前的胸部CT扫描是在 使用最近开发的CT分析技术参数响应映射(PRM)对这些士兵进行子集 这衡量了吸气和呼气扫描之间的肺密度差异。在这里，我们提供第一个 DR-CB的组织病理学特征与异常的放射学特征有关的证据表明 功能性小气道病(FSAD)。我们展示了强迫振荡技术(FOT)，一种肺功能 测试，也可以非侵入性地识别部署的退伍军人的小气道疾病。我们提供更多数据 证明DR-CB的关键组织病理学特征在转基因小鼠模型中得到重现 对位于呼吸道上皮内的祖细胞俱乐部细胞可诱导的、特异的和持续的损伤。这一发现 更多的相关证据表明，在部署过程中存在的许多呼吸道毒素 它们通过俱乐部细胞损伤途径产生有害影响。我们进一步证明了凋亡的俱乐部细胞的增加 纤维化前巨噬细胞聚集在慢性毛细支气管炎的发病机制中。我们的集体数据和 拟议的研究解决了更好地了解、诊断和治疗DR-CB的迫切需要。] 假设：[我们假设退伍军人DR-CB的组织病理学特征表现为 PRM和FOT可发现的功能增强的小气道疾病。我们进一步假设 小鼠球状细胞损伤所致慢性毛细支气管炎的组织病理学特征与细胞凋亡的关系 触发肺巨噬细胞蓄积和促纤维化激活的细胞负荷。] 目标1：确定PRM是否将fSAD的增加确定为放射学替代[对于 定义]DR-CB的组织病理学异常。为此，我们将获得全面的数据集(包括 高分辨率CT扫描)对经过临床指征的GW和9/11后退伍军人的队列 范德比尔特大学医学中心和新泽西战争对不明原因呼吸困难的评估 相关疾病和伤害研究中心。我们将首先对退伍军人的PRM分类进行量化 DR-CB的组织病理学证据，并确定有助于诊断的PRMfSAD的预测阈值 这一条件(目标1a)。然后我们将使用这个阈值来比较未经活组织检查的海湾战争和 9/11后退伍军人DR-CB放射学证据(目标1b)和评估PRMfSAD之间的关系 和FOT(目标1c)。] 目的2：确定持续棍棒致小鼠慢性毛细支气管炎的组织病理学特征 细胞损伤可以通过破坏促纤维化的巨噬细胞对凋亡的反应来预防和(或)改善 细胞。使用我们的小鼠模型，我们将首先确定俱乐部细胞损伤、凋亡细胞负荷、 氧化应激和肺巨噬细胞表型(AIM 2a)，然后确定CD36是否被阻断 (目标2b)或阿奇霉素(目标2c)可预防和(或)解决小鼠慢性毛细支气管炎。] 退伍军人受益：[PRM和FOT技术的应用将显著提高我们的安全能力 诊断DR-CB，从而提前评估其在已部署退伍军人中的流行率，包括 患有海湾战争退伍军人的疾病。我们对俱乐部细胞损伤的重点调查将增进我们对 DR-CB的发病机制应对多种呼吸系统危害并加速发展 对这种衰弱状况进行预防性或积极的治疗。]

Rationale. An increased incidence of respiratory complaints has been identified in Veterans of the Gulf War (GW) [and post-9/11 conflicts. An inhalational injury is suspected given numerous potential exposures to airway toxins. A landmark study (1) in 2011 described a cohort of post-9/11 soldiers with unexplained dyspnea and impaired exercise tolerance that underwent surgical lung biopsy; findings showed evidence of chronic inflammation surrounding thickened fibrotic bronchioles referred to as deployment related chronic bronchiolitis (DR-CB) in this proposal. We performed a preliminary analysis of chest CT scans previously obtained on a subset of these soldiers using parametric response mapping (PRM), a recently-developed CT analytic technique that measures differential lung density between inspiratory and expiratory scans. Here we provide the first evidence linking the histopathologic features of DR-CB with an abnormal radiographic signature indicative of functional small airways disease (fSAD). We show that forced oscillation technique (FOT), a pulmonary function test, may also non-invasively identify small airways disease in deployed Veterans. We provide additional data demonstrating that key histopathologic features of DR-CB are recapitulated in a transgenic murine model of inducible, specific, and sustained injury to progenitor club cells located within the airway epithelium. This finding and additional associational evidence indicate that numerous airway toxins present during deployment mediate their deleterious effects via a club cell injury pathway. We further implicate an increase in apoptotic club cells and profibrotic macrophage accumulation in the pathogenesis of chronic bronchiolitis. Our collective data and proposed studies address an urgent need to better understand, diagnose, and treat DR-CB.] Hypothesis: [We hypothesize that the histopathologic features of DR-CB in Veterans are manifested as increased functional small airways disease detectable by PRM and FOT. We further hypothesize that the histopathologic features of chronic bronchiolitis induced by club cell injury in mice result from increased apoptotic cell burden which triggers accumulation and profibrotic activation of lung macrophages.] Aim 1: To determine whether PRM identifies an increase in fSAD as a radiographic surrogate [for the histopathologic abnormalities that define] DR-CB. In this Aim, we will obtain comprehensive data sets (including high resolution CT scans) on cohorts of GW and Post-9/11 Veterans that underwent clinically-indicated evaluations for unexplained dyspnea at the Vanderbilt University Medical Center and the New Jersey War Related Illness and Injury Study Center. We will first quantify PRM classifications in Veterans with histopathologic evidence of DR-CB and identify a predictive threshold of PRMfSAD that may aid in the diagnosis of this condition (Aim 1a). We will then use this threshold to compare cohorts of non-biopsied Gulf War and Post-9/11 Veterans for radiographic evidence of DR-CB (Aim 1b) and assess relationships between PRMfSAD and FOT (Aim 1c).] Aim 2: To determine whether [histopathologic features of murine chronic bronchiolitis caused by sustained club cell injury can be prevented and (or) ameliorated by disrupting profibrotic macrophage responses to apoptotic cells. Using our murine model, we will first identify relationships between club cell injury, apoptotic cell burden, oxidative stress, and lung macrophage phenotype (Aim 2a) and thereafter determine whether CD36 blockade (Aim 2b) or azithromycin (Aim 2c) can prevent and (or) resolve chronic bronchiolitis in mice.] Benefit to Veterans: [The application of PRM and FOT technology will significantly improve our ability to safely diagnose DR-CB and thus advance assessment of its prevalence amongst deployed Veterans, including those with Gulf War Veterans Illness. Our focused investigation on club cell injury will enhance our understanding of DR-CB pathogenesis in response to numerous respiratory hazards and expedite the development of preventative or active treatments for this debilitating condition.]