ROLE OF NITRIC OXIDE AND INTERLEUKIN 1

气管支气管上皮是肺的动态参与者 生理学和反应，包括清除吸入的 材料，炎症反应的调节和协调 修复。它已经被一些实验室证明 呼吸道上皮细胞具有一种诱导性一氧化氮， 一氧化氮合酶（iNOS）。此外，已经表明，严重的 上皮的损伤是由于暴露于炎性 细胞因子、白细胞介素-1（IL-1）和呼吸道上皮细胞， 以类似于巨噬细胞的方式， 炎症刺激。 现在很明显， 由IL-1引起的上皮细胞病理学是由于 呼吸道上皮细胞过度产生一氧化氮（NO） 本身 在哮喘中，炎症是一个关键的决定因素， 气道功能，并与广泛的上皮细胞 损伤 这项研究计划旨在评估生产 IL-1和NO在哮喘气道中的表达， 在NO介导的损伤中，IL-1和NO对上皮细胞 修复和治疗干预的可能性。 在 检验IL-1和NO重要的中心假设 哮喘炎症中气道上皮损伤的介质， 将集中努力实现以下四个具体目标： I.哮喘与正常人IL-1和NO的细胞来源 航空公司.本节中的实验将评估 假设IL-1和NO的产生是在 哮喘炎症 ELISA，生化分析， 免疫组织化学和原位杂交将用于 检测上皮和非上皮细胞中的这些介质， 小鼠以及哮喘患者的细胞和组织样本中， 患者 二.哮喘气道上皮损伤的途径。的 有待检验假设是， 哮喘中的上皮依赖于局部产生的IL-1。的 将在哮喘动物模型中研究IL-1的作用， IL-1缺乏小鼠的特别优势。组织将 评估是否存在坏死或凋亡， 评估正在进行的细胞损伤可能影响 IL-1信号的性质和持续性。 三.呼吸道上皮对IL-1的反应。的假设 本节提出的是急性和/或慢性 哮喘气道炎症的特点是由IL-1- 触发性损伤，这是显着介导的上皮NO 生产用培养的细胞和 分离的动物和人气管组织将用于 评估损伤的细胞特异性，细胞损伤的途径， 死亡和上皮修复反应。 四.治疗干预。实验设计用于测试 抑制IL-1的产生或作用的假说 和/或NO的产生将显著减少气道 在气道超敏反应的动物模型中的上皮损伤， 预期应用于哮喘患者。

The tracheobronchial epithelium is a dynamic participant in lung physiology and responses, including clearance of inhaled materials, regulation of inflammatory responses, and orchestration of repair. It has been demonstrated by a number of laboratories that respiratory epithelial cells possess an inducible nitric oxide synthase (iNOS). In addition, it has been shown that severe damage to the epithelium results from exposure to an inflammatory cytokine, interleukin-1 (IL-1), and respiratory epithelial cells, in a fashion similar to macrophages, can produce IL-1 in response to inflammatory stimuli. It is now becoming apparent that the epithelial cytopathology caused by IL-1 is due to triggering of overproduction of nitric oxide (NO) by the respiratory epithelium itself. In asthma, inflammation is a critical determinant of disturbed airway function and is associated with widespread epithelial injury. This research plan is designed to evaluate the production of IL-1 and NO in asthmatic airways, the pathway and specificity of NO-mediated damage, the effects of IL-1 and NO on epithelial repair, and possibilities for therapeutic intervention. In testing the central hypothesis that IL-1 and NO are important mediators of airway epithelial damage in asthmatic inflammation, effort will be focused on the following four specific aims: I. Cellular sources of IL-1 and NO in asthmatic and normal airways. The experiments in this section will evaluate the hypothesis that IL-1 and NO production are upregulated in asthmatic inflammation. ELISA, biochemical assays, immunohistochemistry and in situ hybridization will be used to detect these mediators in epithelial and non-epithelial cells from mice, as well as in cell and tissue samples from asthmatic patients. II. Pathway of epithelial damage in asthmatic airways. The hypothesis to be tested is that damage to the respiratory epithelium in asthma is dependent on locally produced IL-1. The role of IL-1 will be studied in an animal model of asthma, taking particular advantage of IL-1-deficient mice. Tissues will be evaluated for the presence of necrosis or apoptosis to permit an assessment of the way in which ongoing cell injury may influence the nature and persistence of the IL-1 signal. III. Respiratory epithelial responses to IL-1. The hypothesis proposed in this section is that acute and/or chronic characteristics of asthmatic airway inflammation result from IL-1- triggered damage, which is significantly mediated by epithelial NO production. In vitro experiments with cultured cells and with explanted animal and human tracheal tissue will be used to evaluate cellular specificity of damage, the pathway of cell death, and epithelial repair responses. IV. Therapeutic intervention. Experiments are designed to test the hypothesis that inhibiting the production or effects of IL-1 and/or the generation of NO will significantly reduce airway epithelial damage in animal models of airway hypersensitivity, anticipating application to asthmatic patients.