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， 作为一个积极的参与者，在促炎和 哮喘的支气管扩张剂生物学 作为一种促炎介质，NO可以 介导气道上皮组织损伤，可能是由于其 氧化成过氧亚硝酸根，OONO，这是一种剧毒阴离子。 NO可能 还与NO和稳定形式的 NO，如亚硝基硫醇，介导气道松弛和抑制 支气管血管渗漏。 已经确定混合的呼出空气 从非哮喘个体中回收。 在哮喘患者中， 糖皮质激素治疗，但不使用支气管扩张剂，或 支气管收缩药物，导致混合呼出NO水平降低。 这些观察促使我们提出以下假设： 由气道酶促产生的NO既作为呼吸道炎症的指标， 气道的炎症微环境，并作为这一介质 炎症以这种方式促进气道阻塞， 高反应性 为了验证这一假设，我们提出了三个具体目标。 上 具体目标，我们将确定肺功能与 中度哮喘患者队列的混合呼气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， 混合呼出气中的NO含量，这将先于肺功能的减退。 在第二组患者中，将获得气道活检， 分析以确定哪些细胞由于所述细胞周期而改变其表型。 类固醇戒断 在第三个具体目标中，我们将检验假设 NO的微环境可用性有助于改变 支气管激发后的气道反应和反应性 吸入性过敏原 为了验证这一假设，我们将研究 抑制气道中NO的酶促产生， 吸入NOS抑制剂对NO生成和肺功能的影响。 在我们的第三 具体目标我们将测试这一假设，即内源性产生的NO 作为气道阻塞和高反应性的介质， 慢性稳定型哮喘，通过测定 吸入NO合成酶抑制剂对呼出的NO水平、气道阻塞 和气道反应性。 这些数据将使我们能够 确定混合呼出的NO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， 作为一种促炎分子。

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.