PATHOGENIC MECHANISM IN PULMONARY INFLAMMATION

肺部炎症的致病机制

• 批准号: 6272603
• 负责人: CHARLES G COCHRANE
• 金额: $ 14.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6272603
• 关键词: adult respiratory distress syndrome; biological signal transduction; blocking antibody; cytokine; disease /disorder model; human subject; inflammation; interleukin 1; interleukin 8; laboratory rabbit; leukocyte activation /transformation; lipopolysaccharides; lung injury; lung lavage; macrophage inflammatory proteins; membrane permeability; molecular pathology; polymerase chain reaction; protein structure function; pulmonary surfactants; receptor binding; tumor necrosis factor alpha

We will continue exploration of the potential role of cytokines in the development of lung injury, utilizing experimental models and assessment of bronchoalveolar lavage fluid from human beings with ARDS. The relationship of tumor necrosis factor (TNF), IL-1, IL-8 and macrophage inflammatory proteins (MIF's) to leukocytic accumulation and stimulation in the lungs will be assessed in rabbit models. Clear definition of the interaction of IL-8 and its receptors on leukocytes will be essential in order to interrupt this crucial step. Cloned IL-8 and IL-8 mutants, bearing mutations in the N-terminal and C- terminal regions, outside of the cysteine bridges, have been constructed. These will be assessed for binding to cells bearing IL-8 receptors A and B and to induce a signal transduction. In addition, synthetic peptides, derived from the N- and C- terminal regions found by mutational analyses to be critical, will be used to block the interactions. Antibodies, constructed to region of IL-8 found to be crucial for the interaction of IL-8 and related molecules with these receptors, will be used to block in vitro IL-8 and MIP-receptor interactions and modulate IL-8 responses in vivo in two rabbits models of ARDS. Bronchoalveolar lavage fluids from patients with ARDS will be assessed for evidence of cytokine activity. The effect of exogenous surfactant on these cytokines will be examined.

我们将继续探索细胞因子在肿瘤发生中的潜在作用。 肺损伤的发展，利用实验模型和评估 支气管肺泡灌洗液的样本 的 肿瘤坏死因子（TNF）、IL-1、IL-8与巨噬细胞的关系 炎症蛋白（MIF）对白细胞积聚和刺激的影响 将在兔模型中评估肺中的细胞毒性。 IL-8及其受体在细胞内相互作用的明确定义 白细胞将是必不可少的，以中断这一关键步骤。 克隆的IL-8和IL-8突变体，在N-末端和C-末端具有突变， 已经构建了半胱氨酸桥之外的末端区域。 将评估它们与携带IL-8受体A和 B并诱导信号转导。 此外，合成肽， 来自突变分析发现的N-和C-末端区域 将被用来阻止相互作用。 针对IL-8区域构建的抗体被发现对免疫应答至关重要。 IL-8和相关分子与这些受体的相互作用， 用于阻断体外IL-8和MIP-受体相互作用并调节 两种家兔急性呼吸窘迫综合征模型体内IL-8反应的研究 将评估ARDS患者的支气管肺泡灌洗液 寻找细胞因子活性的证据 外源性表面活性剂的作用 将检查这些细胞因子。