Airway Reactivity and Heterogeneity in Asthma

哮喘的气道反应性和异质性

• 批准号: 6864355
• 负责人: KENNETH R LUTCHEN
• 金额: $ 59.65万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6864355
• 关键词: asthma; bronchomotion; clinical research; elasticity; human subject; inflammation; lung imaging /visualization /scanning; magnetic resonance imaging; muscle contraction; muscle tone; patient oriented research; respiratory airflow measurement; respiratory function; respiratory hypersensitivity

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.

描述（由申请人提供）：本提案将确定从孤立气道平滑肌（ASM）研究中出现的关于气道高反应性（AHR）的假设是否与原位和人类哮喘相关，强调重度与轻度至中度哮喘患者之间的对比。过去的研究表明，周期性拉伸孤立的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器官的重塑。这一假设推断出炎症的作用，但并没有走到需要它的地步。此类ASM异常应表现为深度吸气（DI）时气道扩张能力降低，以及非均匀性收缩，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明显增加和低氧血症。虽然抑制健康受试者的DI似乎会增强其反应性，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，并且通过随后的DI更容易解决。因此，我们建议测试两个关键假设：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，这样深吸气不能产生持续的支气管扩张，也不能解决异质性。推论1：在健康受试者中禁用DI并不能充分模拟哮喘气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来放大气道的高反应性，导致肌肉僵硬和收缩性增加。推论：随着炎症的增加，DI扩张气道或减少异质性的能力减弱。为了验证这些假设，我们将综合三种先进技术：1)实时跟踪气道阻力（气道口径的替代物），从而使我们能够分析平滑肌张力和气道壁刚度的变化；2)通过动态肺阻力和弹性的频率依赖性跟踪力学异质性；3)应用超极化氦磁共振成像（HP 3He MRI）创建全肺图像，显示异质性和非通气肺泡区。我们的研究将证实AHR是否仅仅需要减少气道平滑肌的拉伸长度，或者气道网络中的炎症和重塑异常作为一个系统也是长期维持增加的僵硬、张力和异质性所必需的，这些都是唯一抵抗DI的。这些研究是将分离平滑肌和细胞水平的理论和实验转化为哮喘气道系统整体水平的关键一步。通过确定对治疗有反应的受试者的显著特征是否恢复和/或维持使用DI调节气道口径的能力，将推进哮喘的治疗和诊断；这种能力反映了治疗可以恢复一个更柔软、反应更少的气道系统。