Responses of Contracted Airways and Parenchyma to Stretch in Vivo

有人认为，哮喘患者对深度吸气的气道收缩反应，与健康人正常的气道扩张相比，反映了这种疾病的内在病理生理学。尽管很明显，这种功能差异必须与呼吸道平滑肌的性质有关，但围绕着呼吸道的实质的性质可能也同样重要。这一事实表明，哮喘的一个重要问题可能与其动态实质环境中的气道平滑肌行为有关。这项建议将评估这种实质-呼吸道相互作用的基础机制，特别是对肺充气和收缩顺畅的深度吸气的反应。 肌肉。该项目包含了几种独特的方法，以提供有关肺部如何在体内对扩张做出反应的新信息。首先，我们使用一种新的方法来挑战单个呼吸道，该方法允许我们分离激动剂刺激对单个呼吸道、整个呼吸道树或肺实质的影响。其次，通过同时使用CT成像和肺阻抗测量，我们将能够完整地描述呼吸道和动态实质粘性和弹性反应。第三，通过使用一种新的激发方法来麻醉局部呼吸道神经，我们可以确定这些神经如何相互作用来确定 深度吸气后，呼吸道是否会收缩或松弛。这一建议的具体目的是为了在体内测试与这种呼吸道-实质相互作用相关的两个主要假说：1)肺充气后呼吸道的结果取决于对平滑肌的相反物理和化学作用之间的平衡；2)实质收缩可以限制因药物或充气压力而导致的气道狭窄的能力。

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.