INFLAMMATION ON AIRWAY CONSTRICTION AND ASTHMA

气道收缩和哮喘的炎症

• 批准号: 2826077
• 负责人: KENNETH R LUTCHEN
• 金额: $ 29.59万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2826077
• 关键词: active immunization; allergens; asthma; biomechanics; bronchoconstrictors; clinical research; human subject; immunologic skin test; inflammation; mathematical model; methacholine; morphology; muscle function; pulmonary respiration; respiratory airflow disorder; respiratory airflow measurement; respiratory airway pressure; respiratory hypersensitivity; respiratory muscles; smooth muscle; spirometry; sputum

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.

哮喘患者气道炎症和异常力学性质之间的关系尚不清楚。 在体内气道的伸展可以减少对激发的稳态收缩反应，并且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，在深吸气（DI）后扩张气道的能力降低;和（B）在支气管激发期间禁止DI导致健康受试者显示哮喘样高反应性。 哮喘患者的炎症会影响气道壁和实质栓系从而抑制平滑肌伸展吗？ 这个问题不能回答从孤立的肌肉准备，有一个缺乏的数据检查这些机制在原位，并与足够的分辨率外周收缩条件。假设1：炎症抑制深吸气时气道平滑肌的伸展。 为了验证这一假设，我们提出了一种方法，可以跟踪气道阻力（原始），气道平滑肌拉伸的指数，在深吸气（DI）期间和之后的高时间分辨率。 肌肉拉伸程度和收缩反射恢复将作为气道炎症程度（独立测定）和收缩程度的函数进行评价。 了解哮喘病情的主要是确定气道收缩和炎症如何协同作用，以建立外周收缩的平均水平和异质性（模式）。 我们将证明，尽管气道阻力Raw增加相对较小，但特定形式的异质收缩可以在典型呼吸速率下产生肺阻力和弹性（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，由于实质与气道分离，严重哮喘的气道炎症使肺易于发生这种根本性的收缩。 假设2：炎症可引起自发性哮喘性收缩病症，这与非炎症环境中哮喘诱导的收缩病症不同。 我们将表明，收缩的模式往往可以推断出从RL和EL的频率依赖性周围的典型呼吸频率。 我们已经开发出一种方法，即使在血流受限的患者中，也可以常规采集此类数据。 我们提出了三项研究，并将在每项研究中进行炎症的细胞测定：研究1将通过在乙酰甲胆碱激发期间禁止深吸气来诱导健康受试者中的哮喘样高反应性，然后跟踪Raw和收缩条件（即，RL和EL的频率依赖性）。 研究2将对具有广泛的预先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激发，并比较在晚期收缩（其中“产生”大量炎症）前后的这些测量结果。 我们将回答：哮喘患者的气道平滑肌是如何起作用的？基于孤立肌肉研究的假设与哮喘相关吗？ 因此，我们将塑造炎症和收缩之间的因果关系的新范式。