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.

哮喘患者中气道炎症与异常机械性能之间的关系知之甚少。气道的体内拉伸可以减少对挑衅的稳态收缩反应，并且可能是气道音调的重要调节器。最近的研究表明，（a）随着哮喘的严重程度增加，在深度灵感（DI）之后，呼吸道的能力降低；（b）禁止在支气管挑战期间进行DI导致健康受试者表现出哮喘样的过度反应性。哮喘患者的炎症会影响气道壁和实质束缚以抑制平滑肌拉伸吗？这个问题不能从孤立的肌肉制剂中回答，并且数据原位检查了这些机制，并且可以充分解决外围收缩条件。假设1：炎症抑制了深度灵感期间气道平滑肌拉伸。为了检验该假设，我们提出了一种可以跟踪气道阻力（RAW）的方法，这是气道平滑肌拉伸的索引，并在深度灵感（DI）期间和之后具有高度分辨率（DI）。肌肉拉伸和反射恢复的程度将作为气道炎症程度（独立分析）和收缩程度评估。理解哮喘状况的主要是确定气道狭窄和炎症是如何共同起作用的，以确定外围收缩的平均水平和异质性（模式）。我们将表明，尽管气道阻力的增加相对较小，但原始的呼吸速率相对较小，但原始的呼吸速率却相对较小，但特定形式的异质收缩可以以典型的肺阻力和弹性（RL和EL）的形式大大增加。这不是直观的，但很重要。我们的证据进一步表明，通过将实质与气道解耦，严重哮喘的气道炎症使这种根本性的收缩形式易于肺部。假设2：炎症会导致自发性哮喘收缩条件与非炎症环境中的药理诱导的收缩条件不同。我们将证明，通常可以从RL和EL的频率依赖性来推断收缩模式对于典型呼吸率的频率。我们已经开发了一种方法来常规获取此类数据，即使在流动限制的患者中也是如此。我们提出了三项研究，并将在每种研究中进行炎症进行细胞测定：研究1将通过禁止在甲基苯胺挑战期间禁止深层灵感在健康受试者中引起哮喘的过度反应性，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将对具有广泛存在的基线炎症的哮喘志愿者进行类似的测量。研究3将对哮喘患者进行抗原挑战，并比较在后期收缩之前和之后的这些测量值，在后期收缩中，“产生了大量的炎症”。然后，我们将回答：气道平滑肌如何在哮喘中发挥作用？并且是否基于与哮喘有关的孤立肌肉研究的假设？因此，我们将在炎症与收缩之间的因果关系上塑造新的范式。