Alveolar macrophage dysregulation in the pathogenesis of Gulf War respiratory illness

背景资料：波斯湾战争20多年后，多达25万名退伍军人仍受到 慢性疾病。在最初的研究中，使人虚弱的呼吸道症状被忽略了。然而，呼吸道 已发现炎症，肺泡巨噬细胞丰富，弥漫性收缩。 毛细支气管炎，可能与部署相关的吸入有关，但没有感染性病原学。然而，只有 对海湾战争呼吸系统疾病(GWRI)的潜在发病机制进行了有限的调查 肺泡巨噬细胞和呼吸道微生物群在GWRI中的作用尚不清楚。 我们小组发现了严重的肺泡巨噬细胞功能障碍是COPD发病的基础。 慢性阻塞性肺疾病患者的肺泡巨噬细胞对细菌抗原的反应明显减弱。易加重 成人COPD患者的肺泡巨噬细胞功能明显减弱。此外， COPD肺泡巨噬细胞对呼吸道病原体具有基本的吞噬缺陷，即直接 与慢性阻塞性肺疾病的进展有关。而先天免疫反应受损和肺功能下降 作为COPD的组成部分，它们不是COPD独有的，而是突出了肺泡的关键潜在贡献 巨噬细胞功能障碍与多种炎症性肺部疾病的进展。 假设：肺泡巨噬细胞-微生物的动态相互作用是肺炎发病的基础 海湾战争呼吸系统疾病。 具体目标：实现以下具体目标： 目的1：研究有无呼吸道疾病的海湾战争疾病患者的呼吸道微生物群特征。 目的2：阐明肺泡巨噬细胞先天免疫功能障碍在海湾战争呼吸系统疾病中的作用 以及与呼吸道微生物群组成的关系。 目的3：阐明特定部署暴露、人口统计学和呼吸系统疾病之间的关系 海湾战争病。 研究设计：由于GWRI是一种人类独有的疾病，这些研究是用肺泡设计的 从海湾战争参与者身上获得的巨噬细胞。将招募四组志愿者。第1组：GWI 有呼吸道症状。2组：无呼吸道症状GWI组。第三组：海湾战争退伍军人 任何一次世界大战的证据。第四组：非海湾战争退伍军人。第三组和第四组为海湾地区提供了重要的控制 战争曝光。每个参与者都将接受支气管肺泡灌洗。目标1将是第一次对 GWRI的肺微生物群。在目标2中，肺泡巨噬细胞吞噬功能的差异，TLR-2和-4 炎症和转录组表达的调节将在不同组之间确定，并将 结合目标1的结果，开始探索呼吸道微生物群之间的动态相互作用 和GWRI的免疫功能障碍。在目标3中，人口和部署暴露，以及肺功能 将进行调查，并将与目标1和目标2的结果相结合。 影响：目前还没有确定的治疗GWRI的方法，也没有确定的抗生素益处， 支气管扩张剂或类固醇。对这一建议的研究旨在确定分类群或分类群的组合， 不仅与肺泡巨噬细胞功能异常有关，而且与从广泛的 免疫阵列。这种方法有望调节选定的肺泡巨噬细胞功能。 通过转移肺部微生物区系，一种彻底改变了艰难梭菌结肠炎治疗的方法。我们 这项提议的预期结果将导致通过微生物群调节肺泡巨噬细胞的功能 在GWRI中进行修复，这是一种旨在阻止疾病进展的全新方法。 这项研究的总体目标是确定基本的、可修改的监管固有防御 肺泡巨噬细胞在GWRI中的作用机制，作为治疗靶点和改善临床结果。

Background: Over two decades following the Persian Gulf War, up to 250,000 veterans are still plagued by chronic conditions. Debilitating respiratory symptoms were neglected in initial studies. However, airway inflammation with abundant of alveolar macrophages has been discovered, along with diffuse constrictive bronchiolitis, possibly associated with deployment-related inhalation, but with no infectious etiology. Yet, only limited investigation into the underlying pathogenesis of Gulf War respiratory illness (GWRI) has been undertaken and the role of alveolar macrophages and the airway microbiome in GWRI remains unexplored. Our group has discovered severe alveolar macrophage dysfunction underlying the pathogenesis of COPD. Alveolar macrophages in COPD are dramatically hyporesponsive to bacterial antigens. Exacerbation-prone adults with COPD have significantly diminished pathogen-induced alveolar macrophage function. Moreover, COPD alveolar macrophages have a fundamental phagocytic defect for respiratory pathogens that is directly linked to progression of COPD. While impaired innate immune responses and decline in lung function are integral to COPD, they are not unique to COPD, but rather highlight the key potential contribution of alveolar macrophage dysfunction to progression of numerous inflammatory lung diseases. Hypothesis: Dynamic alveolar macrophage-microbial interactions are fundamental to the pathogenesis of Gulf War respiratory disease. Specific Aims: The following specific aims will be accomplished: Aim 1: Characterize the human airway microbiome of Gulf War Illness with and without respiratory disease. Aim 2: Elucidate the role of alveolar macrophage innate immune dysfunction in Gulf War respiratory illness and the relationship with airway microbiome composition. Aim 3: Elucidate the relationship of specific deployment exposures, demographics and respiratory disease in Gulf War Illness. Research Design: As GWRI is an exclusively human disease, these studies are designed using alveolar macrophages obtained from Gulf War participants. Four groups of volunteers will be recruited. Group 1: GWI with respiratory symptoms. Group 2: GWI without respiratory symptoms. Group 3: Gulf War veterans without any evidence of GWI. Group 4: non-Gulf War veterans. Groups 3 and 4 provide important controls for Gulf War exposures. Each participant will undergo bronchoalveolar lavage. Aim 1 will be the first investigation into the lung microbiome of GWRI. In Aim 2, differences in alveolar macrophage phagocytosis, TLR-2 and -4 regulation of inflammation and of transcriptome expression will be determined between groups, and will be integrated with results from Aim 1 to begin to explore the dynamic interplay between the airway microbiome and immune dysfunction in GWRI. In Aim 3, demographic and deployment exposures, and pulmonary function will be investigated and will be integrated with results of Aims 1 and 2. Impact: There are no established therapeutics for GWRI and no established benefit from antibiotics, bronchodilators or steroids. Studies of this proposal are directed at identifying taxa or combinations of taxa, associated not just with aberrant alveolar macrophage functions, but with select functions chosen from a broad immunologic array. This approach holds the promise of modulation of select alveolar macrophage function through transfer of lung microbiota, an approach that has revolutionized the treatment of C. difficile colitis. We anticipate results of this proposal will lead to regulation of alveolar macrophage function through microbiome restoration in GWRI, a completely novel approach aimed at interrupting the progression of disease. The overall goal of this research is to identify fundamental, modifiable regulatory innate defense mechanisms of alveolar macrophages in GWRI, to serve as therapeutic targets and improve clinical outcomes.