NITRIC OXIDE AS AN INDICATOR AND MEDIATOR OF AIRWAY INFLAMMATION

一氧化氮(NO)是一种多功能的生物介质，已被 作为促炎和致炎的积极参与者 哮喘的支气管扩张剂生物学。作为一种促炎介质，没有人可以 介导呼吸道上皮组织损伤，可能是由于其 氧化成过氧亚硝酸盐，Oono，这是一种剧毒的阴离子。不，五月。 也在体内平衡中发挥作用，同时具有NO和稳定形式的 NO，如亚硝硫醇，介导呼吸道松弛和抑制 支气管血管渗漏。已经确定混合后的呼出空气 从非哮喘患者中康复。在哮喘患者中， 使用糖皮质激素治疗，但不使用支气管扩张剂或 支气管收缩药，导致混合过期NO水平下降。 这些观察结果促使我们提出以下假设： 由呼吸道酶促产生的NO既是一种指示物，也是 气道炎性微环境及其中介作用 炎症，以促进呼吸道阻塞和 高反应性。 为了验证这一假设，我们建议追求三个具体目标。在第一个 具体目的我们将确定肺功能与 在一组中度哮喘患者中混合过期的NO水平 停用吸入性糖皮质激素治疗后的一段时间。 如果我们的假设是正确的，我们预计将观察到水平的增加 混合呼出空气中的NO，这将先于肺功能的下降。 在第二组患者中，将获得呼吸道活组织检查和 分析以确定哪些细胞由于 停用类固醇。在第三个具体目标中，我们将检验这一假设 NO的微环境可获得性有助于改变 支气管刺激后的呼吸道反应和反应性 吸入过敏原。为了检验这一假设，我们将检验 通过使用An抑制呼吸道中NO的酶促生成 吸入一氧化氮合酶抑制剂，对NO生成和肺功能的影响。在我们的第三个 我们将测试这一假设，即内生产生NO 作为呼吸道阻塞和高反应性的媒介 安慰剂治疗慢性稳定期哮喘的疗效观察 吸入一氧化氮合酶抑制剂，以缓解呼吸困难， 和呼吸道反应性。综合起来，获得的数据将使我们能够 确定混合过期一氧化氮是否是哮喘的先兆指标 如果NO本身实际上参与了炎症反应 作为促炎分子的过程。

Nitric oxide (NO) is a multifunctional biological mediator that has been implicated as an active participant in both the proinflammatory and the bronchodilator biology of asthma. As a proinflammatory mediator, NO can mediate airway epithelial tissue damage, probably by virtue of its oxidation to peroxynitrite, OONO, which is a highly toxic anion. NO may also function in a homeostatic role with both NO and stabilized forms of NO, such as nitrosothiols, mediating airway relaxation and inhibiting bronchovascular leak. It has been established that the mixed expired air recovered from nonasthmatic individuals. In individuals with asthma, treatment with glucocorticoid but not with bronchodilator or bronchoconstrictor drugs, results in a decrease in mixed expired NO levels. These observations prompt us to offer the following hypothesis: NO produced enzymatically by the airway serves both as an indicator of the inflammatory microenvironment of the airway and as a mediator of this inflammation in such a way as to promote airway obstruction and hyperresponsiveness. To test this hypothesis we propose to pursue 3 specific aims. In the first specific aim we will determine the relationship between lung function and mixed expired NO levels in a cohort of patients with moderate asthma in the period following withdrawal from treatment with inhaled glucocorticoids. If our hypothesis is correct, we expect to observe increases in the level of NO in mixed expired air, which will precede decrements in lung function. On a second cohort of patients airway biopsies will be obtained and analyzed to determine which cells change their phenotype as a result of the steroid withdrawal. In the third specific aim we will test the hypothesis that the microenvironmental availability o NO contributes to changes in airway responses and responsiveness following bronchoprovocation with inhaled allergen. To test this hypothesis we will examine the effects of inhibiting the enzymatic production of NO in the airways, by using an inhaled NOS inhibitor, on NO production and lung function. In our third specific aim we will test this hypothesis that endogenously produced NO serves as a mediator of airway obstruction and hyperresponsiveness in chronic stable asthma by determining the effects of treatment with an inhaled NO synthase inhibitor on expired levels of NO, airway obstruction, and airway responsiveness. Together the data obtained will allow us to determine if mixed expired NO is a premonitory indicator of asthma exacerbation and if the NO itself actually participates in the inflammatory process as a pro-phlogistic molecule.