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

推进海湾战争退伍军人与部署相关的慢性肺病的无创诊断和治疗

• 批准号: 9890135
• 负责人: JOHN OSTERHOLZER
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890135
• 关键词: Academic Medical Centers; Address; Age; Animal Model; Animals; Apoptotic; Asia; Azithromycin; Biopsy; Bronchioles; Bronchiolitis; CD36 gene; Cells; Characteristics; Chronic; Chronic lung disease; Classification; Clinical; Clinical Trials; Collaborations; Conflict (Psychology); Data; Data Reporting; Data Set; Development; Diagnosis; Diagnostic radiologic examination; Disease; Dyspnea; Epithelial Cells; Evaluation; Exercise; Exercise Tolerance; Exposure to; Fibrosis; Future; Gender; Gulf War; High Resolution Computed Tomography; Impairment; Incidence; Inflammation; Inhalation; Injury; Investigation; Link; Literature; Lung; Measures; Mediating; Mus; New Jersey; Operative Surgical Procedures; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Phenotype; Prevalence; Preventive treatment; Pulmonary Emphysema; Pulmonary function tests; Receptor Cell; Reporting; Research Personnel; Resort; Respiratory Signs and Symptoms; Scanning; Soldier; Spirometry; Techniques; Terminal Bronchiole; Testing; Toxin; Transgenic Organisms; Veterans; War; X-Ray Computed Tomography; active method; airway epithelium; airway inflammation; cell injury; chest computed tomography; cohort; density; hazard; human model; improved; lung injury; macrophage; mouse model; noninvasive diagnosis; novel; prevent; progenitor; pulmonary function; respiratory; respiratory toxin; response; severe injury; small airways disease; technology/technique; translational study

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.]

理由。海湾战争退伍军人中呼吸道疾病的发病率增加 (GW)[9/11后的冲突。考虑到大量潜在的气道暴露，怀疑吸入性损伤 毒素2011年的一项具有里程碑意义的研究（1）描述了一组9/11后的士兵，他们患有不明原因的呼吸困难， 接受手术肺活检的运动耐量受损;结果显示慢性 增厚的纤维化细支气管周围的炎症，称为展开相关慢性细支气管炎 （D-CB）在这份提案中。我们对以前在一个 这些士兵的子集使用参数响应映射（PRM），最近开发的CT分析技术 测量吸气和呼气扫描之间的肺密度差异。在这里，我们提供了第一个 将DR-CB的组织病理学特征与异常放射学特征联系起来的证据表明 功能性小气道疾病（fSAD）。我们表明，强迫振荡技术（FOT），肺功能 测试，也可以非侵入性地确定部署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重现， 对位于气道上皮内的祖细胞俱乐部细胞的诱导性、特异性和持续性损伤。这一发现 另外的相关证据表明，在展开过程中存在的许多气道毒素介导 它们通过俱乐部细胞损伤途径的有害作用。我们进一步暗示凋亡的俱乐部细胞增加， 和促纤维化巨噬细胞积聚在慢性细支气管炎发病机制中的作用。我们的集体数据和 提出的研究解决了更好地理解、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可检测到的功能性小气道疾病增加。我们进一步假设， 凋亡细胞增多致棒状细胞损伤小鼠慢性毛细支气管炎病理组织学特征 细胞负荷，其触发肺巨噬细胞的积聚和促纤维化活化。] 目的1：确定PRM是否将fSAD增加识别为放射学替代[对于 定义DR-CB的组织病理学异常。在本目标中，我们将获得全面的数据集（包括 高分辨率CT扫描）对GW和9/11后退伍军人队列进行临床指征 在范德比尔特大学医学中心和新泽西战争中对不明原因呼吸困难的评估 相关疾病和伤害研究中心。我们将首先量化退伍军人中的PRM分类， DR-CB的组织病理学证据，并确定可能有助于诊断的PRMfSAD的预测阈值 这一点（目标1a）。然后，我们将使用这个阈值来比较海湾战争的非活检队列， 9/11后退伍军人的DR-CB（目标1b）影像学证据，并评估PRMfSAD之间的关系 （目标1c）。 目的2：探讨慢性支气管炎小鼠的组织病理学特征 细胞损伤可以通过破坏促纤维化巨噬细胞对细胞凋亡的应答来预防和（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CD 36阻断是否 (Aim目的2b）或阿奇霉素（Aim 2c）可预防和（或）缓解小鼠慢性毛细支气管炎。 对退伍军人的好处：[PRM和FOT技术的应用将显着提高我们的安全能力， 诊断DR-CB，从而提前评估其在部署的退伍军人中的患病率， 海湾战争退伍军人病我们对俱乐部细胞损伤的集中研究将提高我们对 DR-CB的发病机制在应对众多的呼吸危害和加快发展， 预防或积极治疗这种衰弱的条件。