Regional Gas Trapping in Bronchoconstricted Asthmatics

支气管收缩性哮喘中的区域气体滞留

• 批准号: 6793294
• 负责人: Jose G Venegas
• 金额: $ 48.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6793294
• 关键词: asthma; bronchospasm; clinical research; histamine; human subject; lung; methacholine; positron emission tomography; respiratory airway volume; respiratory function; respiratory pharmacology

Asthma is a disease of increasing incidence that already affects more than 17 million people in the United States alone. It is therefore of major importance to understand the mechanisms responsible for the underlying mechanical and physiological changes that occur during asthma exacerbations. The long-term objective of this project is to expand the understanding of these mechanisms and provide the foundations upon which to develop improved methods for diagnosing, monitoring and managing asthma. Specifically, this proposal will study the phenomenon of airway closure and gas trapping (GT) during bronchoconstriction (BC). Total closure of pulmonary airways resulting in distal GT has long been suspected to occur in asthma and has been proposed as a major mechanism contributing to the impairment of gas exchange and increased work of breathing during severe BC. Unfortunately, until recently, there has only been indirect evidence about airway closure and direct observation of closed airways during whole-lung BC has remained elusive. Using Positron Emission Tomography (PET) we demonstrated the development of large contiguous areas of pulmonary GT in broncho-constricted animals and in an asthmatic subject. These data are consistent with segment-size ventilation defects recently visualized with MRI in asymptomatic asthmatics. The main hypotheses guiding this proposal are: 1) the changes in pulmonary mechanics during severe BC in asthma can be explained in great part by airway closure and distal gas trapping and 2) the pattern of heterogeneity in ventilation (VA) and GT during asthmatic BC should be considerably affected by heterogeneous constriction of large pulmonary airways. Our novel PET imaging technique measures the local elimination kinetics of an IV injected saline solution bolus of the isotope gas Nitrogen-13 (13 NN) and yields three- dimensional data on the topographic distribution of pulmonary perfusion (Q) and VA, and on the location and extent of gas trapped regions within the lung. We plan to use this technique, in combination with sophisticated oscillatory mechanics measurements, in normal subjects and in symptomatic and asymptomatic asthmatics, in order to achieve the following specific aims: 1) Assess the relationship between changes in global lung mechanics and in the topographic distribution of VA, and the length scale and extent of GT, during agonist-induced BC. And 2) Quantify the contribution of factors affecting the temporal and spatial constancy of these local effects such as the heterogeneous distribution of the agonist and the history of lung expansion. The experimental data to be gathered is expected to provide unique insights in the process of BC in asthma and this will serve to validate and refine the theoretical models of gas exchange and lung mechanics required to develop advanced methodologies for the diagnosis, monitoring and management of asthma.

哮喘是一种发病率不断增加的疾病，仅在美国就已经影响了1700多万人。因此，了解哮喘急性发作期间发生的潜在机械和生理变化的机制至关重要。 该项目的长期目标是扩大对这些机制的理解，并为开发诊断、监测和管理哮喘的改进方法提供基础。具体而言，本提案将研究支气管收缩（BC）期间的气道闭合和气体捕获（GT）现象。长期以来，人们一直怀疑导致远端GT的肺气道完全关闭会发生在哮喘中，并已提出这是导致严重BC期间气体交换受损和呼吸功增加的主要机制。 不幸的是，直到最近，只有间接的证据表明气道关闭和直接观察关闭气道在全肺BC仍然难以捉摸。 使用正电子发射断层扫描（PET），我们证明了大的连续区域的肺GT的支气管收缩的动物和哮喘的主题的发展。 这些数据与最近在无症状哮喘患者中通过MRI观察到的节段性通气缺陷一致。 本研究的主要假设是：1）哮喘严重BC期间的肺力学变化在很大程度上可以通过气道关闭和远端气体捕获来解释; 2）哮喘BC期间通气（VA）和GT的异质性模式应受到大肺气道不均匀收缩的显著影响。 我们的新型PET成像技术测量IV注射的同位素气体氮-13（13 NN）的盐水溶液团注的局部消除动力学，并产生关于肺灌注（Q）和VA的地形分布以及关于肺内气体截留区域的位置和程度的三维数据。 我们计划在正常受试者和有症状及无症状哮喘患者中使用这种技术，结合复杂的振动力学测量，以实现以下特定目标：1）评估激动剂诱导的BC期间整体肺力学变化和VA地形分布变化之间的关系，以及GT的长度尺度和范围。和2）量化影响这些局部效应的时间和空间恒定性的因素的贡献，例如激动剂的不均匀分布和肺扩张的历史。 收集的实验数据有望为哮喘的BC过程提供独特的见解，这将有助于验证和完善气体交换和肺力学的理论模型，以开发用于诊断、监测和管理哮喘的先进方法。