NITRIC OXIDE AS AN INDICATOR AND MEDIATOR OF AIRWAY INFLAMMATION

一氧化氮作为气道炎症的指标和介质

• 批准号: 6433740
• 负责人: Jeffrey Mark Drazen
• 金额: $ 22.59万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6433740
• 关键词: asthma; biomarker; clinical research; drug withdrawal; enzyme inhibitors; glucocorticoids; human subject; human therapy evaluation; inflammation; nitric oxide; nitric oxide synthase; oxidative stress; respiratory airflow disorder; respiratory function; respiratory hypersensitivity; respiratory therapy

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.

一氧化氮（NO）是一种多功能的生物介体 被视为促炎和的活跃参与者 哮喘的支气管扩张剂生物学。 作为促炎的调解人，没有 介导气道上皮组织损伤，可能是由于其 氧化为过氧硝酸盐，OONO，这是一种剧毒阴离子。 没有 同样在稳态角色中发挥作用，既没有稳定的形式 不，例如硝基硫醇，介导气道放松和抑制 支气管血管泄漏。 已经确定混合过期的空气 从非肢体个体中恢复过来。 在患有哮喘的人中 用糖皮质激素治疗，但不使用支气管扩张剂或 支气管收缩药物导致混合过期的NO水平降低。 这些观察结果促使我们提供以下假设： 气道通过酶酶酶的产生既可以用作 气道的炎症微环境和作为此的调解人 炎症以促进气道阻塞和 反应性过高。 为了检验这一假设，我们建议追求3个具体目标。 在第一个 具体目的，我们将确定肺功能与 混合在一组中度哮喘的患者中未过期 退出吸入糖皮质激素治疗后的时期。 如果我们的假设是正确的，我们希望观察到水平的增加 在混合过期的空气中NO，该空气将在肺功能下降之前。 将获得第二个患者的同类，将获得气道活检和 分析以确定哪些细胞因 类固醇提取。 在第三个特定目的中，我们将检验假设 微环境可用性o没有任何促进 呼吸道的响应和响应能力在支气管前后 吸入过敏原。 为了检验这一假设，我们将研究 通过使用一个 吸入的NOS抑制剂，无生产和肺功能。 在我们的第三个 具体目的，我们将检验以内源性产生否的假设 充当气道阻塞和反应性的调解人 慢性稳定哮喘通过确定用 在过期的NO，气道阻塞的水平上吸入NO合成酶抑制剂， 和气道响应能力。 共同获得的数据将使我们能够 确定混合过期的NO是否是哮喘的预先指标 加剧，如果没有，则实际上会参加炎症 作为促剂分子的过程。