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）：该提案将确定从孤立的气道平滑肌（ASM）研究中出现的有关气道高反应性（AHR）的假设是否与现场和人类哮喘相关，强调了严重与轻度至中度性哮喘患者之间的对比度。过去的研究表明，孤立的ASM的周期性拉伸会减少肌肉对挑衅的收缩反应，而缺乏伸展会导致更硬，更收缩的肌肉。他们假设哮喘患者中的AHR是由于ASM的慢性缩短异常而导致其收缩仪的重塑。该假设不断发挥炎症的作用，但并不需要它。 ASM异常应该通过降低的能力来表现出来，以降低灵感（DI）（DI）和异质收缩，包括与DI无法分辨的气道关闭的限制。这种异质性可能导致呼吸和低氧血症的工作显着增加。虽然抑制健康受试者的DI似乎会扩大其反应性，但我们的初步数据表明，通过调用其他机制和以随后的DI为单位的方式来解决其他机制。因此，我们建议检验两个关键的假设：1）哮喘患者的过度反应性要求气道平滑肌驻留在独特的僵硬，收缩的状态下，这样深度的灵感不能产生持续的支气管扩张状态或异质性的分辨率。推论1：禁止在健康受试者中进行DI，不能充分模仿与气道哮喘中气道高反应性相关的机制。 2）炎症通过气道平滑肌肉张力和缩短而扩大气道高反应性，从而增加肌肉僵硬和收缩力。推论：随着炎症的增加，DI降低了气道或减少异质性的能力。为了检验这些假设，我们将综合三种高级技术：1）实时跟踪气道阻力，一种替代气道口径的替代物，从而使我们能够测定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机械异质性； 3）应用超极化的氦磁共振成像（HP 3HE MRI）创建全肺图像，显示出异质性和非通风牙槽区域。我们的研究将确认AHR是否需要简单地减少气道平滑肌的长度，或者是气道网络中的炎症和重塑异常，作为系统，对于长期维持较长的刚度，音调和异质性，这些系统具有较长的僵硬，对DI的抗性。这些研究是将分离的平滑肌和细胞水平转化为整个哮喘气道系统水平的理论和实验的关键步骤。通过确定那些对治疗响应的受试者的区别特征是否是恢复和/或维持使用DI调节气道口径的能力来提出哮喘治疗和诊断；反映治疗可以恢复较软，响应迅速的气道系统的能力。