ROLE OF NITRIC OXIDE AND INTERLEUKIN 1

气管、支气管上皮是肺的动态参与者 生理和反应，包括吸入物的清除 材料、炎症反应的调节和协调 修理的问题。许多实验室已经证明了这一点。 呼吸道上皮细胞具有诱导性硝酸根 一氧化氮合酶(INOS)。此外，已经表明，严重的 上皮损伤是由于暴露在炎性物质中造成的。 细胞因子、白介素1(IL-1)和呼吸道上皮细胞， 以类似巨噬细胞的方式，可以产生IL-1作为反应 对炎性刺激。现在越来越明显的是， IL-1引起的上皮细胞病理改变是由于触发了 呼吸道上皮细胞产生过量的一氧化氮(NO) 它本身。 在哮喘中，炎症是紊乱的关键决定因素。 呼吸道功能与广泛的上皮性病变相关 受伤。这项研究计划是为了评估产品 IL-1和NO在哮喘呼吸道中的表达及其途径和特异性 关于NO介导的损伤，IL-1和NO对上皮细胞的影响 修复，以及治疗干预的可能性。在……里面 检验IL-1和NO重要的中心假设 哮喘炎症中呼吸道上皮损伤的介质， 将集中努力实现以下四个具体目标： I.哮喘和正常人IL-1和NO的细胞来源 航空公司。本节中的实验将评估 IL-1和NO产生上调的假说 哮喘性炎症。酶联免疫吸附试验，生化检测， 免疫组织化学和原位杂交将用于 检测上皮性细胞和非上皮性细胞中的这些介质 小鼠以及哮喘患者的细胞和组织样本中 病人。 哮喘呼吸道上皮损伤的途径。这个 需要检验的假设是对呼吸系统的损害 哮喘的上皮细胞依赖于局部产生的IL-1。这个 IL-1的作用将在哮喘动物模型中进行研究，服用 IL-1缺陷小鼠的独特优势。纸巾将成为 评估是否存在坏死或凋亡，以允许 评估持续的细胞损伤可能影响的方式 IL-1信号的性质和持久性。 呼吸道上皮细胞对IL-1的反应假说 在本节中提出的是急性和/或慢性 IL-1-1致哮喘气道炎症的特点 触发的损伤，这在很大程度上是由上皮细胞NO介导的 制作。培养细胞的体外实验和 移植的动物和人类气管组织将用于 评估损伤的细胞特异性，即细胞的途径 死亡和上皮修复反应。 四、治疗性干预。实验的设计是为了测试 抑制IL-1的产生或作用的假说 和/或NO的产生将显著减少呼吸道 呼吸道过敏症动物模型的上皮损伤， 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.