Airway Reactivity and Heterogeneity in Asthma

描述(由申请者提供)：这项建议将建立分离的呼吸道平滑肌(ASM)研究中出现的关于呼吸道高反应性(AHR)的假说是否与原位和人类哮喘相关，强调重度和轻中度哮喘患者之间的对比。过去的研究表明，周期性地拉伸孤立的ASM会降低肌肉对刺激的收缩反应，而缺乏拉伸会导致肌肉更僵硬、更收缩。他们假设哮喘患者的AHR是由于ASM的异常慢性缩短导致其收缩装置的重塑。这一假设推断了炎症的作用，但还没有到需要这种作用的程度。这种ASM异常应该表现为深吸气性(DI)下的气道扩张能力降低和异质性收缩，包括无法通过DI解决的气道关闭。这种异质性可导致呼吸功显著增加和低氧血症。虽然在健康受试者中抑制DI似乎会放大他们的反应性，但我们的初步数据表明，这是通过调用额外的机制来实现的，而且这种方式对后续的DI更容易解决。因此，我们建议检验两个关键假设：1)哮喘患者的高反应性要求气道平滑肌处于一种独特的僵硬、收缩状态，这样深度吸入既不能产生持续的支气管扩张，也不能消除异质性。结论1：在健康受试者中禁止DI并不能充分模拟与哮喘的呼吸道高反应性相关的条件和机制。2)炎症通过持续增加气道平滑肌张力和缩短而增强气道高反应性，导致肌肉僵硬和收缩能力增加。推论：随着炎症的增加，DI扩张呼吸道或减少异质性的能力降低。为了验证这些假设，我们将综合三项先进技术：1)实时跟踪气道阻力，以替代气道口径，从而使我们能够分析平滑肌张力和气道壁硬度的变化；2)通过动态肺阻力和弹性的频率依赖性跟踪机械异质性；以及3)应用超极化氦磁共振成像(HP3He MRI)创建全肺图像，揭示异质性和非通气性肺泡区。我们的研究将证实AHR是否需要简单地减少气道平滑肌的伸展长度，或者作为一个系统的气道网络中的炎症和重塑异常是否也是长期维持唯一抵抗DI的僵硬、张力和异质性所必需的。这些研究是将分离的平滑肌和细胞水平的理论和实验转化为哮喘呼吸道系统整体水平的关键一步。哮喘的治疗和诊断将通过确定对治疗有反应的受试者的区别特征是否恢复和/或维持利用DI调节气道口径的能力；反映治疗可以恢复更柔软、反应较慢的呼吸道系统的能力来推进哮喘的治疗和诊断。

DESCRIPTION (provided by applicant): This proposal will establish whether hypotheses that have emerged from isolated airway smooth muscle (ASM) studies regarding airway hyperreactivity (AHR) are relevant in situ and in human asthma, emphasizing the contrast between severe versus mild-to-moderate asthmatics. Past studies have shown that periodic stretching of isolated ASM reduces the muscle's contractile response to provocation whereas lack of stretching results in a stiffer, more contractile muscle. They hypothesize that AHR in asthmatics results from abnormal chronic shortening of the ASM resulting in remodeling of its contractile apparatus. This hypothesis infers a role for inflammation but does not go so far as to require it. Such ASM abnormalities should manifest themselves via a reduced capacity to dilate airways with a deep inspiration (DI) and heterogeneous constriction inclusive of airway closures that are not resolvable with a DI. Such heterogeneities can result in marked increase in the work of breathing and in hypoxemia. While inhibiting a DI in healthy subjects seems to amplify their reactivity, our preliminary data suggest it does so by invoking additional mechanisms and in a manner that is more resolvable with a subsequent DI. Hence, we propose to test two key hypotheses: 1) Hyperreactivity in asthmatics requires that the airway smooth muscle reside in a uniquely stiff, contractile state such that deep inspirations cannot produce sustained bronchodilation nor resolution of heterogeneities. Corollary 1: Prohibiting a DI in healthy subjects does not sufficiently mimic conditions and mechanisms associated with airway hyperreactivity in asthma. 2) Inflammation amplifies airway hyperreactivity via a sustained increase in airway smooth muscle tone and in shortening, leading to increased muscle stiffness and contractility. Corollary: With increased inflammation, a DI is less able to dilate airways or reduce heterogeneity. To test these hypotheses we will synthesize three advanced technologies: 1) Tracking of airway resistance, a surrogate for airway caliber, in real time thus allowing us to assay changes in smooth muscle tone and airway wall stiffness; 2) Tracking mechanical heterogeneity via the frequency dependence of dynamic lung resistance and elastance; and 3) Applying hyperpolarized helium magnetic resonance imaging (HP 3He MRI) to create whole-lung images that reveal heterogeneity and non-ventilated alveolar regions. Our studies will confirm whether AHR requires simply reduced length stretching of airway smooth muscle, or whether inflammatory and remodeling abnormalities in the airway network as a system are also necessary to chronically sustain increased stiffness, tone, and heterogeneities that are uniquely resistant to a DI. These studies are a crucial step in translating theories and experiments at the level of isolated smooth muscle and cells to the level of the asthmatic airway system as a whole. Asthma treatment and diagnosis will be advanced by establishing whether the distinguishing feature in those subjects that respond to treatments is reinstatement and/or sustenance of the capacity to modulate airway caliber with a DI; a capacity reflecting that the treatment can restore a softer, less responsive airway system.