Airway Reactivity and Heterogeneity in Asthma

哮喘的气道反应性和异质性

• 批准号: 7172948
• 负责人: KENNETH R LUTCHEN
• 金额: $ 53.42万
• 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/7172948
• 关键词: Accounting; Acute; Affect; Airway Resistance; Allergic; Alveolar; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Atelectasis; Behavior; Biological Assay; Breathing; Bronchodilation; Caliber; Caring; Chemicals; Chronic; Clinical; Closure; Condition; Constriction procedure; Data; Defect; Dependence; Depth; Diagnosis; Diagnostic; End Point; Environment; Environmental air flow; Frequencies; Gases; Helium; Heterogeneity; Hospitals; Hour; Human; Hypoxemia; Image; In Situ; Inflammation; Inflammatory; Laboratory Research; Length; Lung; Magnetic Resonance Imaging; Measures; Mechanical ventilation; Mechanics; Muscle; Muscle Tonus; Muscle function; Nature; Pathology; Phase; Process; Prohibit; Rate; Research; Research Personnel; Resistance; Resolution; Role; Smooth Muscle; Smooth Muscle Myocytes; Standards of Weights and Measures; Stretching; System; Technology; Testing; Time; Translating; Trees; Woman; Work; Work of Breathing; airway hyperresponsiveness; airway inflammation; antigen challenge; asthmatic airway; base; cost; human data; human subject; in vivo; lung imaging; novel; research study; respiratory smooth muscle; response; restoration; theories

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的气道平滑肌（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之间的对比。过去的研究表明，孤立的ASM的周期性拉伸减少了肌肉对刺激的收缩反应，而缺乏拉伸导致肌肉更僵硬，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。这一假说推断炎症的作用，但并没有走得太远，需要它。这种ASM异常应表现为通过减少的能力，以扩大气道与深吸气（DI）和不均匀的收缩，包括气道关闭，是不能解决的DI。这种异质性可导致呼吸功的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，这是通过调用其他机制来实现的，并且以一种更容易与随后的DI一起解决的方式来实现。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独特的僵硬、收缩状态，使得深吸气不能产生持续的支气管扩张，也不能消除异质性。推论一：在健康受试者中禁止DI不能充分模拟与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降低。为了验证这些假设，我们将综合三种先进的技术：1）在真实的时间内跟踪气道阻力，气道口径的替代物，从而允许我们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）应用超极化氦磁共振成像（HP 3 He MRI）建立全肺图像，显示不均匀性和非通气肺泡区域。我们的研究将证实AHR是否需要简单地减少气道平滑肌的长度拉伸，或者气道网络作为一个系统的炎症和重塑异常是否也是长期维持增加的刚度、张力和异质性所必需的，这些都是唯一抵抗DI的。这些研究是将分离的平滑肌和细胞水平的理论和实验转化为整个哮喘气道系统水平的关键一步。将通过确定对治疗有反应的受试者的区别特征是否是恢复和/或维持DI调节气道口径的能力来推进哮喘治疗和诊断;这种能力反映了治疗可以恢复更柔软、反应性更低的气道系统。