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，了解哮喘加重期间发生的潜在的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了解，并为开发更好的诊断、监测和管理哮喘的方法提供基础。具体地说，这项建议将研究支气管收缩(BC)过程中的呼吸道关闭和气体捕获(GT)现象。在哮喘患者中，一直怀疑完全关闭肺通道导致远端GT，并被认为是导致重度BC时气体交换障碍和呼吸功增加的主要机制。不幸的是，直到最近，只有间接证据表明呼吸道闭合，在全肺BC期间直接观察闭合的气道仍然难以捉摸。利用正电子发射断层扫描(PET)，我们证实了在支气管收缩的动物和哮喘受试者中肺GT的大范围连续区域的发展。这些数据与最近在无症状哮喘患者中MRI显示的节段大小的呼吸缺陷是一致的。本文提出的主要假设是：1)哮喘重症BC期间的肺力学改变在很大程度上可以用气道闭合和远端气体捕获来解释；2)哮喘BC期间的通气量(VA)和GT的异质性模式应受到大肺大通道的异质性收缩的很大影响。我们的新的PET成像技术测量了静脉注射的同位素气体氮-13(13NN)的盐水溶液团注的局部消除动力学，并产生了关于肺灌注(Q)和VA的地形分布以及肺内气体捕获区域的位置和范围的三维数据。我们计划在正常受试者以及有症状和无症状的哮喘患者中使用这项技术，并结合复杂的振荡力学测量，以实现以下特定目的：1)评估激动剂诱导的BC期间，整体肺力学变化和VA的地形图分布以及GT长度、规模和程度之间的关系。以及2)量化影响这些局部效应的时间和空间稳定性的因素的贡献，如激动剂的异质性分布和肺扩张历史。预计将收集的实验数据将为哮喘的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，这些模型是开发先进的哮喘诊断、监测和管理方法所需的。

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.