INFLAMMATION ON AIRWAY CONSTRICTION AND ASTHMA

哮喘患者的呼吸道炎症和异常机械性能之间的关系还知之甚少。在体内，气道的伸展可以减弱对刺激的稳态收缩反应，这可能是气道张力的重要调节器。最近的研究表明：(A)随着哮喘严重程度的增加，深吸气(DI)后扩张呼吸道的能力减弱；(B)在支气管激发期间禁止DI会导致健康受试者表现出哮喘样的高反应性。哮喘患者的炎症是否会影响气道壁和实质拴系以抑制平滑肌伸展？这个问题不能从分离的肌肉标本中得到回答，而且缺乏在原位检验这些机制的数据，并且对外周收缩条件有足够的分辨率。假设1：在深度吸气时，炎症抑制了呼吸道平滑肌的伸展。为了验证这一假设，我们提出了一种方法，可以在深吸气(DI)过程中和之后以高时间分辨率跟踪呼吸道阻力(Raw)，这是一种呼吸道平滑肌伸展的指标。肌肉拉伸的程度和收缩的反射恢复将作为呼吸道炎症程度(独立检测)和收缩程度的函数来评估。了解哮喘病情的基本原则是确定气道收缩和炎症如何协同作用，以确定外周收缩的平均水平和异质性(模式)。我们将展示特殊形式的异质收缩可以在典型的呼吸频率下产生肺阻力和弹性(RL和EL)的大幅增加，尽管气道阻力Raw的增加相对较小。这不是直观的，但很重要。我们的证据进一步表明，通过将实质与呼吸道分离，严重哮喘的呼吸道炎症使肺易于发生这种根本形式的收缩。假设2：炎症可导致自发性哮喘收缩状态不同于非炎症环境中药物引起的收缩状态。我们将证明，收缩模式通常可以从RL和EL对典型呼吸频率周围的频率的依赖关系中推断出来。我们已经开发了一种常规获取此类数据的方法，即使是在血流受限的患者中也是如此。我们提出了三项研究，并将在每项研究中进行炎症的细胞分析：研究1将通过禁止在乙酰甲胆碱激发期间深度吸入在健康受试者中诱导哮喘样高反应，然后跟踪在DI期间和之后的Raw和收缩条件(即RL和EL的频率依赖性)。研究2将在哮喘志愿者身上进行类似的测量，这些志愿者之前存在广泛的基线炎症。研究3将对哮喘患者进行抗原挑战，并比较晚期收缩前后的这些测量结果，在晚期收缩中，“产生”实质性炎症。然后我们将回答：哮喘患者的呼吸道平滑肌功能如何？基于分离肌肉研究的假说是否与哮喘相关？因此，我们将在炎症和收缩之间的因果关系上塑造新的范式。

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.