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INFLAMMATION ON AIRWAY CONSTRICTION AND ASTHMA

气道收缩和哮喘的炎症

基本信息

批准号：
6537542
负责人：
KENNETH R LUTCHEN
金额：
$ 32.27万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2005-03-31
项目状态：
已结题

项目摘要

The relation between airway inflammation and abnormal mechanical properties in asthmatics is poorly understood. In vivo stretching of airways can diminish the steady-state constriction response to a provocation and may be an important modulator of airway tone. Recent studies indicate that (a) with increased severity of asthma, there is a diminished capacity to dilate airways following a deep inspiration (DI); and (b) prohibiting a DI during a bronchial challenge causes healthy subjects to show asthmatic-like hyperresponsiveness. Could inflammation in asthmatics affect airway walls and parenchymal tethering to inhibit smooth muscle stretching? This question cannot be answered from isolated muscle preparations, and there is a paucity of data examining these mechanisms in situ, and with sufficient resolution to the peripheral constriction conditions. HYPOTHESIS 1: Inflammation inhibits airway smooth muscle stretching during a deep inspiration. To test this hypotheses we propose a method that can track airway resistance (Raw), an index of airway smooth muscle stretching, with high time resolution during and after a deep inspiration (DI). Degree of muscle stretch and reflex recovery of constriction will be evaluated as a function of the degree of airway inflammation (assayed independently) and the degree of constriction. Principal to understanding the asthmatic condition is to determine how airway constriction and inflammation act in concert to establish both the mean level and the heterogeneity (pattern) of peripheral constriction. We will show that particular forms of heterogeneous constriction can produce large increases in lung resistance and elastance (RL and EL) at typical breathing rates, despite relatively small increases in airway resistance, Raw. This is not intuitive, but important. Our evidence further suggests that by decoupling parenchyma from airways, airway inflammation in severe asthma predisposes the lung for this radical form of constriction. HYPOTHESIS 2: Inflammation can cause spontaneous asthmatic constriction conditions to be distinct from pharmacologically induced constriction conditions in a non-inflammatory environment. We will show that the pattern of constriction can often be inferred from the frequency dependence of RL and EL for frequencies surrounding typical breathing rates. We have developed a method to routinely acquire such data, even in flow-limited patients. We propose three studies and will perform a cellular assay for inflammation in each: Study 1 will induce asthmatic-like hyperresponsiveness in healthy subjects by prohibiting deep inspirations during a methacholine challenge and then track Raw and the constriction conditions (i.e., frequency dependence of RL and EL) during and after a DI. Study 2 will perform similar measurements on asthmatic volunteers with a wide range of pre-existing baseline inflammation. Study 3 will perform an antigen challenge on asthmatics and compare these measurements before and after a late-phase constriction in which substantial inflammation is "created". We will answer then: How does airway smooth muscle function in an asthmatic?; and Are hypotheses based on isolated muscle studies relevant to asthma? Thus, we will mold new paradigms on the causality link between inflammation and constriction.

哮喘患者气道炎症与异常力学性能之间的关系尚不清楚。在体内，气道的伸展可以减少对刺激的稳态收缩反应，可能是气道张力的重要调节剂。最近的研究表明(a)随着哮喘严重程度的增加，深度吸气（DI）后气道扩张能力减弱；(b)在支气管攻击期间禁止使用DI会导致健康受试者表现出类似哮喘的高反应性。哮喘患者的炎症是否会影响气道壁和实质栓系从而抑制平滑肌伸展？这个问题不能从孤立的肌肉准备中得到回答，并且缺乏原位检查这些机制的数据，并且对周围收缩条件有足够的分辨率。假设1：深度吸气时炎症抑制气道平滑肌伸展。为了验证这一假设，我们提出了一种方法，可以跟踪气道阻力（Raw），气道平滑肌拉伸的指标，在深度吸气（DI）期间和之后具有高时间分辨率。肌肉伸展程度和收缩的反射恢复将作为气道炎症程度（独立分析）和收缩程度的函数来评估。了解哮喘的主要条件是确定气道收缩和炎症如何协同作用，以确定周围收缩的平均水平和异质性（模式）。我们将表明，在典型呼吸速率下，尽管气道阻力增加相对较小，但特定形式的非均匀收缩可以产生肺阻力和弹性（RL和EL）的大幅增加。这不是直观的，但很重要。我们的证据进一步表明，通过将实质与气道分离，严重哮喘的气道炎症使肺容易发生这种激进形式的收缩。假设2：炎症可引起自发性喘息性收缩，不同于非炎症环境下药物诱导的收缩。我们将表明，收缩的模式通常可以从RL和EL对典型呼吸频率周围频率的频率依赖中推断出来。我们已经开发出一种常规获取此类数据的方法，即使在流量有限的患者中也是如此。我们提出了三个研究，并将在每个研究中对炎症进行细胞分析：研究1将在健康受试者中通过在甲胆碱刺激期间禁止深吸气来诱导哮喘样高反应性，然后在DI期间和之后跟踪Raw和收缩条件（即RL和EL的频率依赖性）。研究2将对患有哮喘病的志愿者进行类似的测量。研究3将对哮喘患者进行抗原激发，并在“产生”实质性炎症的晚期收缩前后比较这些测量结果。然后我们会回答：哮喘患者的气道平滑肌是如何起作用的？以及基于孤立肌肉研究的假设是否与哮喘有关？因此，我们将塑造炎症和收缩之间因果关系的新范式。