LIPID PATHWAYS AND LUNG INJURY

脂质通路和肺损伤

• 批准号: 6309901
• 负责人: DAVID BASS
• 金额: $ 3.88万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6309901
• 关键词: adult respiratory distress syndrome; arachidonate; asthma; blood lipid; clinical research; eicosanoid metabolism; human subject; lung injury; molecular pathology; pathologic process

The project does not focus on a single disease but on the mechanisms common to several forms of lung disease. The diseases have in common a mediation by leukocytes, alterations in the activities of lipid mediator pathways (releasing eicosanoids, lysophospholipids, PAF), and lung injury. The global implications of these pathways are emphasized among the projects by the different leukocyte cell types being studied. The function of this core will be to provide human cells from normal donors and from donors with inflammatory lung diseases as appropriate for each Project. Much of the function of the core will involve obtaining samples from normal donors for detailed study in vitro. Normal samples to be obtained will include blood cells (neutrophils, eosinophils, monocytes) and lung cells (isolated by bronchoalveolar lavage (BAL) or endobronchial biopsy or from lung tissue). Samples from patients with asthma and ARDS will also be acquired. ARDS is generally accepted as being primarily mediated by uncontrolled acute inflammation; neutrophil and probably macrophage pathways are hypothesized to play a central role in the pathogenesis of ARDS. In contrast, although neutrophils and macrophages may contribute to asthma, most evidence points to mast cells and eosinophils as being major components of the immediate and late asthmatic responses, respectively. Each project examines specific aspects of these cells and their modulation during the disease(s) which stimulate that specific cell type. In all projects, the format will be to study in detail the pathways in normal cells and in cells modulated in vitro. Neutrophils and macrophages will be studied after priming with endotoxin or TNF, eosinophils after priming with IL-5, and mast cells after binding of IgE. Once the experimental conditions are defined, the investigators will study cells from patients with the disease process which prompted development of the in vitro model in the first place. For example, neutrophils and macrophages from patients with ARDS will be compared with neutrophils and macrophages treated with TNF or IL-1, but eosinophils obtained from blood and BAL during asthma, in particular during the late phase asthmatic response, will be compared with eosinophils primed with IL-5. The main hypothesis is that these specific cells and these cell-specific agonists will activate a common series of lipid pathways within the cells, which in turn contribute to the lung injury. The purpose of this clinical core will be the collection of patient samples and provision of samples to the members of the program project. These samples will include blood, and bronchoalveolar cells and alveolar lining fluid, the latter two obtained by bronchoalveolar lavage (BAL). While the Core will also maintain clinical data on all patients, the focus of this Program is the elucidation of the cellular and biochemical pathways of inflammatory lung injury. Methods: Asthmatic subjects undergo allergen skin testing, inhaled allergen challenge and then endobronchial challenge with collection of bronchoalveolar lavage fluid. The inhaled allergen challenge permits assessment of the presence of a late asthmatic response (LAR) which is likely a reflection of inflammation and its sequellae in contrast to the non-inflammatory early reaction. Normal volunteers and subjects with SIRS and ARDS will also undergo bronchoscopy with BAL.

该项目并不关注单一疾病，而是关注几种肺部疾病的共同机制。 这些疾病的共同点是白细胞介导、脂质介导途径活性的改变（释放类二十烷酸、溶血磷脂、PAF）和肺损伤。 正在研究的不同白细胞类型的项目强调了这些途径的全球影响。 该核心的功能是根据每个项目的情况，提供来自正常捐献者和患有炎症性肺病捐献者的人类细胞。 核心的大部分功能将涉及从正常供体获取样本以进行详细的体外研究。 获得的正常样本包括血细胞（中性粒细胞、嗜酸性粒细胞、单核细胞）和肺细胞（通过支气管肺泡灌洗 (BAL) 或支气管内活检或从肺组织中分离）。 还将采集哮喘和急性呼吸窘迫综合征患者的样本。 人们普遍认为ARDS主要是由不受控制的急性炎症介导的；中性粒细胞和可能的巨噬细胞途径被假设在 ARDS 的发病机制中发挥核心作用。 相比之下，尽管中性粒细胞和巨噬细胞可能导致哮喘，但大多数证据表明肥大细胞和嗜酸性粒细胞分别是立即和晚期哮喘反应的主要组成部分。 每个项目都会检查这些细胞的特定方面及其在刺激特定细胞类型的疾病期间的调节。 在所有项目中，形式将是详细研究正常细胞和体外调节细胞的途径。 将在用内毒素或 TNF 引发后研究嗜中性粒细胞和巨噬细胞，在用 IL-5 引发后研究嗜酸性粒细胞，在 IgE 结合后研究肥大细胞。 一旦确定了实验条件，研究人员将研究患有疾病过程的患者的细胞，这首先促进了体外模型的开发。 例如，来自 ARDS 患者的中性粒细胞和巨噬细胞将与用 TNF 或 IL-1 治疗的中性粒细胞和巨噬细胞进行比较，但在哮喘期间，特别是在哮喘反应的晚期阶段，从血液和 BAL 中获得的嗜酸性粒细胞将与用 IL-5 引发的嗜酸性粒细胞进行比较。 主要假设是这些特定细胞和这些细胞特异性激动剂将激活细胞内一系列常见的脂质途径，进而导致肺损伤。该临床核心的目的是收集患者样本并向计划项目成员提供样本。 这些样本包括血液、支气管肺泡细胞和肺泡内壁液，后两者通过支气管肺泡灌洗 (BAL) 获得。 虽然核心还将维护所有患者的临床数据，但该计划的重点是阐明炎症性肺损伤的细胞和生化途径。方法：哮喘受试者接受过敏原皮肤测试、吸入过敏原激发，然后通过收集支气管肺泡灌洗液进行支气管内激发。 吸入过敏原激发可以评估晚期哮喘反应（LAR）的存在，这可能是炎症及其后遗症的反映，与非炎症早期反应相反。 正常志愿者和患有 SIRS 和 ARDS 的受试者也将接受 BAL 支气管镜检查。