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: 10664925
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664925
• 关键词: Academic Medical Centers; Acceleration; Address; Age; Airway Fibrosis; Animal Experiments; Animal Model; Apoptotic; Asia; Azithromycin; Biopsy; Bronchioles; Bronchiolitis; CD36 gene; Cells; Characteristics; Chronic; Chronic lung disease; Classification; Clinical; Clinical Trials; Collaborations; Conflict (Psychology); Data; Data Set; Development; Diagnosis; Disease; Dyspnea; Epithelial Cells; Evaluation; Exercise; Exercise Tolerance; Exposure to; Fibrosis; Future; Gender; Gulf War; Gulf War veteran; High Resolution Computed Tomography; Human Resources; Impairment; Incidence; Inflammation; Inhalation; Injury; Investigation; Link; Literature; Lung; Macrophage; Maps; 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; mouse model; noninvasive diagnosis; novel; post 9/11; prevent; progenitor; pulmonary function; radiological imaging; 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。在海湾战争的退伍军人中发现了呼吸投诉的发病率增加 （GW）[和9/11后冲突。鉴于气道接触了许多潜在的暴露，怀疑吸入损伤 毒素。一项具有里程碑意义的研究（1）在2011年描述了一群9/11名士兵，其呼吸困难和 接受手术肺活检的运动耐受性受损；调查结果显示了慢性的证据 围绕增厚的纤维化支气管的炎症称为部署相关的慢性支气管炎 （DR-CB）在此提案中。我们对先前在A上获得的胸部CT扫描进行了初步分析 这些士兵使用参数响应映射（PRM）的子集，这是一种最近开发的CT分析技术 这可以衡量吸气和呼气扫描之间的差异肺密度。在这里我们提供第一个 将DR-CB的组织病理学特征与异常的放射线学特征联系起来的证据 功能性小气道疾病（FSAD）。我们表明强迫振荡技术（FOT），一种肺功能 测试，也可能非侵入性地识别部署的退伍军人中的小气道疾病。我们提供其他数据 证明DR-CB的关键组织病理学特征是在一个转基因鼠模型中概括的 可诱导，特异性且持续的损伤位于气道上皮内的祖细胞细胞。这个发现 其他关联证据表明，部署期间存在许多气道毒素 他们通过俱乐部细胞伤害途径的有害影响。我们进一步暗示凋亡俱乐部细胞的增加 慢性支气管炎的发病机理中的纤维巨噬细胞积累。我们的集体数据和 拟议的研究迫切需要更好地理解，诊断和治疗DR-CB。] 假设：[我们假设DR-CB在退伍军人中的组织病理特征被表现为 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 小鼠俱乐部细胞损伤诱导的慢性支气管炎的组织病理学特征是凋亡增加导致的 触发肺巨噬细胞的积累和纤维化激活的细胞负担。] 目标1：确定PRM是否将FSAD的增加确定为放射线造影替代[用于 定义DR-CB的组织病理学异常。在此目标中，我们将获得全面的数据集（包括 高分辨率CT扫描）对经过临床指示的GW和9/11名退伍军人队列 范德比尔特大学医学中心和新泽西战争的无法解释的呼吸困难的评估 相关疾病和伤害研究中心。我们将首先量化退伍军人的PRM分类 DR-CB的组织病理学证据并确定PRMFSAD的预测阈值，该阈值可能有助于诊断 这种情况（AIM 1A）。然后，我们将使用此阈值比较非亲属的海湾战争和 9/11后退伍军人用于DR-CB的射线照相证据（AIM 1B）并评估PRMFSAD之间的关系 和fot（AIM 1C）。] 目的2：确定[鼠慢性支气管炎的组织病理学特征是否由持续俱乐部引起 可以通过破坏对凋亡的纤维化巨噬细胞反应来预防细胞损伤和（或）改善 细胞。使用我们的鼠模型，我们将首先确定俱乐部细胞损伤，凋亡细胞负担之间的关系， 氧化应激和肺巨噬细胞表型（AIM 2A），此后确定CD36封锁是否 （AIM 2B）或阿奇霉素（AIM 2C）可以预防和（或）解决小鼠的慢性支气管炎。] 对退伍军人的好处：[PRM和FOT技术的应用将显着提高我们安全的能力 诊断DR-CB，从而提前评估其部署的退伍军人的患病率，包括 海湾退伍军人病。我们对俱乐部细胞损伤的重点调查将增强我们对 DR-CB发病机理响应许多呼吸危害，并加快了 针对这种使人衰弱的状况的预防或主动治疗。]

项目成果

Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis.

• DOI: 10.1016/j.ajpath.2021.11.012
• 发表时间: 2021-12
• 期刊: The American journal of pathology
• 作者: S. Teitz-Tennenbaum;Steven P. Viglianti;Ahmad Jomma;Q. Palone;H. Andrews;K. Selbmann;S. Lahiri

CD36/Lyn kinase interactions within macrophages promotes pulmonary fibrosis in response to oxidized phospholipid.

• DOI: 10.1186/s12931-023-02629-6
• 发表时间: 2023-12-14
• 期刊: Respiratory research
• 影响因子: 5.8