LIPID PATHWAYS AND LUNG INJURY

该项目的重点不是单一的疾病，而是几种形式的肺部疾病的共同机制。这些疾病有一个共同的介导性因素：白细胞、脂类介体活性的改变(释放二十烷基硫酸酯、溶血磷脂、PAF)和肺损伤。正在研究的不同类型的白细胞在项目中强调了这些途径的全球影响。该核心的功能将是为每个项目酌情提供来自正常捐赠者和患有炎症性肺部疾病的捐赠者的人体细胞。核心的大部分功能将涉及从正常捐赠者那里获取样本，以便在体外进行详细研究。将获得的正常样本将包括血细胞(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)或支气管镜活检或从肺组织分离)。还将获得哮喘和急性呼吸窘迫综合征患者的样本。ARDS被普遍认为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哮喘即刻和晚期反应的主要成分。每个项目都检查这些细胞的特定方面以及它们在疾病期间的调节(S)，这些调节刺激了特定的细胞类型。在所有项目中，格式将是详细研究正常细胞和体外调节细胞中的通路。中性粒细胞和巨噬细胞在内毒素或肿瘤坏死因子预处理后，嗜酸性粒细胞在IL-5预处理后进行研究，肥大细胞在IgE结合后进行研究。一旦确定了实验条件，研究人员将研究患者的细胞，这些患者的疾病过程首先促使了体外模型的发展。例如，ARDS患者的中性粒细胞和巨噬细胞将与经肿瘤坏死因子或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，特别是在哮喘反应后期，从血液和BAL中获得的嗜酸性粒细胞将与经IL-5刺激的嗜酸性粒细胞进行比较。主要的假设是，这些特定的细胞和这些细胞特异的激动剂将激活细胞内一系列共同的脂质途径，这反过来又会导致肺损伤。这个临床核心的目的将是收集患者样本并向计划项目的成员提供样本。这些样本将包括血液、支气管肺泡细胞和肺泡衬里液体，后两者通过支气管肺泡灌洗(BAL)获得。虽然CORE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：哮喘患者先进行变应原皮肤试验、吸入变应原激发，然后收集支气管肺泡灌洗液进行支气管内激发。吸入性变应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，与非炎症性早期反应相反。正常志愿者和患有SIRS和ARDS的受试者也将接受BAL的支气管镜检查。

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.