Lung Inflation and Airway Hyperresponsiveness

肺充气和气道高反应性

• 批准号: 6805858
• 负责人: N FRANKLIN ADKINSON
• 金额: $ 47.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805858
• 关键词: allergens; antihistamines; asthma; bronchoconstrictors; bronchodilators; bronchomotion; chronic obstructive pulmonary disease; clinical research; computed axial tomography; cyclic GMP; human subject; leukotrienes; methacholine; nitric oxide; plethysmography; pulmonary respiration; respiratory airway volume; respiratory epithelium; spirometry

DESCRIPTION (provided by applicant): Airways hyperresponsiveness (AHR) is a central feature of asthma, strongly related to the severity of the disease. However, its mechanisms are not understood. In the first period of this grant, we examined how lung inflation (deep inspiration) influences airways responsiveness. We identified that lung inflation has two distinct beneficial effects in healthy humans: it acts as a bronchoprotector and as a bronchodilator against bronchoconstrictive stimuli. We also found that the bronchoprotective effect of lung inflation is lost in individuals with AHR and is also absent against the bronchoconstriction induced by an allergic reaction. Preliminary findings indicate that the bronchodilatory effect is lost in subjects with COPD and in those with severe asthma. We now propose 3 specific aims: Specific aim 1 will test the hypothesis that nitric oxide (NO), which affects the airways smooth muscle by increasing the levels of cGMP, mediates the bronchoprotective effects of lung inflation and that the NO effect is impaired in AHR. This will be tested with the use of inhaled NO in healthy subjects and subjects with asthma with the intent to demonstrate that NO can mimic deep inspiration-induced bronchoprotection only in the former group. An analogous approach will be used by pre-treatment with sildenafil citrate, an approved inhibitor of PDE V, the enzyme responsible for cGMP degradation. Specific aim 2 will be devoted to the understanding of the mechanisms behind the absence of bronchoprotection against a respiratory allergic reaction. We will first examine whether an allergic reaction leads to the loss of bronchoprotection against other stimuli, such as methacholine. By using inhaled NO, we will examine whether the bronchoprotective action of this molecule is absent against an allergic reaction. With antagonists to products of the allergic reaction (primarily antileukotrienes and antihistamines), we will test whether we can restore the bronchoprotective effects of lung inflation against allergen. In specific aim 3 we will examine the reasons behind the loss of the bronchodilatory effect of lung inflation. Our hypothesis is that, in COPD, bronchodilation is lost as a result of impairment in lung elastic recoil, whereas in severe asthma, as a result of airway wall stiffness. To test this hypothesis, we will investigate these subject groups in comparison to healthy controls by simultaneously testing airways distensibility through high resolution computerized tomography imaging, recoil pressure at various lung volumes and bronchodilation by lung inflation.

描述（由申请人提供）：气道高反应性（AHR）是哮喘的核心特征，与疾病的严重程度密切相关。然而，其机制尚不清楚。在这笔资助的第一阶段，我们研究了肺充气（深吸气）如何影响气道反应性。我们发现，肺膨胀对健康人类有两种明显的有益作用：它充当支气管保护剂和对抗支气管收缩刺激的支气管扩张剂。我们还发现，患有 AHR 的个体肺膨胀的支气管保护作用消失了，并且对于过敏反应引起的支气管收缩也没有作用。初步研究结果表明，慢性阻塞性肺病和严重哮喘患者的支气管扩张作用消失。我们现在提出 3 个具体目标： 具体目标 1 将检验以下假设：一氧化氮 (NO) 通过增加 cGMP 水平影响气道平滑肌，介导肺膨胀的支气管保护作用，并且一氧化氮作用在 AHR 中受损。我们将在健康受试者和哮喘受试者中使用吸入 NO 进行测试，目的是证明 NO 只能在前一组中模拟深吸气诱导的支气管保护作用。类似的方法将使用柠檬酸西地那非进行预处理，西地那非是一种经批准的 PDE V 抑制剂，PDE V 是负责 cGMP 降解的酶。具体目标 2 将致力于了解缺乏针对呼吸道过敏反应的支气管保护作用背后的机制。我们将首先检查过敏反应是否会导致支气管对其他刺激（例如乙酰甲胆碱）的保护作用丧失。通过使用吸入一氧化氮，我们将检查该分子是否缺乏针对过敏反应的支气管保护作用。使用过敏反应产物的拮抗剂（主要是抗白三烯药和抗组胺药），我们将测试是否可以恢复肺膨胀对过敏原的支气管保护作用。在具体目标 3 中，我们将研究肺充气的支气管扩张作用丧失背后的原因。我们的假设是，在慢性阻塞性肺病中，支气管扩张作用的丧失是由于肺弹性回缩力受损，而在严重哮喘中，则是由于气道壁僵硬所致。为了检验这一假设，我们将通过高分辨率计算机断层扫描成像同时测试气道扩张性、不同肺容量的反冲压力以及肺膨胀引起的支气管扩张，从而与健康对照组进行比较来研究这些受试者组。