Regional Gas Trapping in Bronchoconstricted Asthmatics

哮喘是一种发病率越来越高的疾病，仅在美国就已经影响了1700多万人。因此，了解哮喘发作期间发生的潜在机械和生理变化的机制是非常重要的。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）期间气道关闭和气体捕获（GT）现象。长期以来，人们一直怀疑在哮喘中会发生远端GT的肺气道完全关闭，并认为这是导致严重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，只有气道关闭的间接证据和全肺BC期间气道关闭的直接观察仍然难以获得。利用正电子发射断层扫描（PET），我们证实了支气管收缩动物和哮喘患者肺GT大连续区域的发展。这些数据与最近在无症状哮喘患者中MRI显示的节段性通气缺陷一致。指导本研究的主要假设是：1)哮喘严重BC时肺力学的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时通气（VA）和GT的异质性模式应该在很大程度上受到大肺道非均质收缩的影响。我们的新型PET成像技术测量了静脉注射盐水溶液中同位素气体氮-13 （13nn）的局部消除动力学，并产生了肺灌注(Q)和VA的地形分布的三维数据，以及肺内气体捕获区域的位置和范围。我们计划将该技术与复杂的振荡力学测量相结合，用于正常受试者以及有症状和无症状的哮喘患者，以实现以下具体目标：1)评估激动剂诱导BC期间整体肺力学变化与VA地形分布之间的关系，以及GT的长度范围和范围。2)量化影响这些局部效应时空稳定性的因素，如激动剂的异质性分布和肺扩张史。收集的实验数据预计将为哮喘中的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，为哮喘的诊断、监测和管理开发先进的方法。

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.