Responses of Contracted Airways and Parenchyma to Stretch in Vivo

已经表明，与健康受试者中观察到的正常气道扩张相比，哮喘受试者对深吸气的气道收缩反应反映了这种疾病的内在病理生理学。虽然很明显，气道平滑肌的性质必须参与这种功能差异，气道周围的实质的性质可能同样重要。这一事实表明，哮喘的一个重要问题可能与气道平滑肌在其动态实质环境中的行为有关。该建议将评估这种实质-气道相互作用的基础机制，特别关注肺膨胀和收缩平滑的深吸气的反应。 肌肉.该项目包含几种独特的方法，以提供有关肺如何对体内扩张作出反应的新信息。首先，我们使用一种新的方法来挑战单个气道，使我们能够分离激动剂刺激对单个气道、整个气道树或肺实质的影响。其次，通过同时使用CT成像与肺阻抗测量，我们将能够完全表征气道和动态实质粘性和弹性响应。第三，通过使用一种新的激发方法麻醉局部气道神经，我们可以确定这些神经如何相互作用，以确定 呼吸道在深吸气后是否会收缩或舒张。本提案的具体目的是测试与体内气道-实质相互作用相关的两个主要假设：1）肺充气后气道的最终行为取决于对平滑肌的相反物理和化学作用之间的平衡; 2）实质收缩可以限制气道因药理学或充气压力而变窄的能力。

It has been suggested that the airway contractile response of asthmatic subjects to a deep inspiration, compared to normal airway dilation seen in healthy subjects, reflects an intrinsic pathophysiology of this disease. Although it is clear that properties of airway smooth muscle must be involved in this functional difference, the properties of the parenchyma that surround the airways may be equally important. This fact suggests that a significant problem in asthma may be related to airway smooth muscle behavior in its dynamic parenchymal environment. This proposal will evaluate mechanisms that underlie this parenchymal-airway interaction, particularly focused on the response to lung inflation and deep inspiration with contracted smooth muscle. This project contains several unique approaches to provide new information on how the lung responds to distension in vivo. First we use a novel method of challenging individual airways that allows us to separate the effects of agonist stimulation on individual airways, the entire airway tree, or the lung parenchyma. Second, by simultaneously using CT imaging with lung impedance measurements, we will be able to completely characterize the airway and dynamic parenchymal viscous and elastic responses. Third, by using a novel challenge method to anesthetize local airway nerves, we can determine how these nerves interact to determine whether the airway will respond with a contraction or relaxation following a deep inspiration. Specific aims of this proposal are designed to test two primary hypotheses related to this airway-parenchymal interaction in vivo: 1) The resultant behavior of airways following lung inflation depends on a balance between opposing physical and chemical effects on the smooth muscle; 2) parenchymal contraction can limit the ability of airways to narrow with pharmacologic or inflation stresses.