Lung Inflation and Airway Hyperresponsiveness

肺充气和气道高反应性

• 批准号: 7123480
• 负责人: N FRANKLIN ADKINSON
• 金额: $ 30.93万
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123480
• 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)：呼吸道高反应性(AHR)是哮喘的一个中心特征，与疾病的严重程度密切相关。然而，其机制尚不清楚。在这项资助的第一阶段，我们研究了肺充气(深度吸气)如何影响呼吸道的反应性。我们发现，肺膨胀对健康人体有两种不同的益处：一种是支气管保护器，另一种是对抗支气管收缩刺激的支气管扩张剂。我们还发现，肺膨胀对AHR患者的支气管保护作用消失，对过敏反应引起的支气管收缩也缺乏保护作用。初步研究结果表明，在慢性阻塞性肺疾病患者和严重哮喘患者中，这种支气管扩张作用消失。我们现在提出三个特定的目标：特定的目标1将检验这样的假设，即一氧化氮(NO)通过增加cGMP水平影响呼吸道平滑肌，介导肺膨胀的支气管保护作用，并且在AHR中NO的作用受到损害。这一点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度吸入诱导的支气管保护。一种类似的方法将被使用柠檬酸西地那非的预处理，这是一种被批准的PDE V的抑制剂，PDE V是负责cGMP降解的酶。具体目标2将致力于了解对呼吸道过敏反应缺乏支气管保护的机制。我们将首先检查过敏反应是否会导致对其他刺激物(如乙酰甲胆碱)的支气管保护丧失。通过使用吸入的NO，我们将检查该分子是否没有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，我们将研究肺膨胀失去支气管扩张作用背后的原因。我们的假设是，在COPD患者中，由于肺弹性反冲受损而导致的支气管扩张丧失，而在严重哮喘中，则是由于气道壁僵硬所致。为了验证这一假设，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、不同肺容量下的反冲压力和肺充气引起的支气管扩张，并将这些受试组与健康对照组进行比较。

项目成果

Nerve growth factor expression and release in allergic inflammatory disease of the upper airways.

上呼吸道过敏性炎症性疾病中神经生长因子的表达和释放。

• DOI: 10.1164/ajrccm.161.5.9908028
• 发表时间: 2000
• 期刊: American journal of respiratory and critical care medicine.
• 作者: Sanico,AM;Stanisz,AM;Gleeson,TD;Bora,S;Proud,D;Bienenstock,J;Koliatsos,VE;Togias,A
• 通讯作者: Togias,A

Bronchodilation response to deep inspirations in asthma is dependent on airway distensibility and air trapping.

• DOI: 10.1152/japplphysiol.00603.2010
• 发表时间: 2011-02
• 期刊: Journal of applied physiology
• 影响因子: 3.3
• 作者: G. Pyrgos;N. Scichilone;A. Togias;Robert H. Brown

The bronchoprotective effect of deep inspiration is flow rate dependent.

深吸气的支气管保护作用取决于流速。

• DOI: 10.1016/j.rmed.2007.02.001
• 发表时间: 2007
• 期刊: Respiratory medicine
• 影响因子: 4.3
• 作者: Skloot,GwenS;Chandy,Dipak;Schachter,Neil;Togias,Alkis
• 通讯作者: Togias,Alkis

Deep inspiration-induced changes in lung volume decrease with severity of asthma.

深吸气引起的肺容量变化随着哮喘的严重程度而减少。

• DOI: 10.1016/j.rmed.2006.09.009
• 发表时间: 2007
• 期刊: Respiratory medicine
• 影响因子: 4.3
• 作者: Scichilone,Nicola;Marchese,Roberto;Soresi,Simona;Interrante,Amelia;Togias,Alkis;Bellia,Vincenzo
• 通讯作者: Bellia,Vincenzo

Allergen-induced changes in airway responsiveness are not related to indices of airway edema.

过敏原引起的气道反应性变化与气道水肿指数无关。

• DOI: 10.1067/mai.2001.114247
• 发表时间: 2001
• 期刊: The Journal of allergy and clinical immunology.
• 作者: PeeblesJr,RS;Wagner,EM;Liu,MC;Proud,D;Hamilton,RG;Togias,A
• 通讯作者: Togias,A