INFLAMMATORY ALTERATIONS ON AIRWAY MECHANICS IN VIVO

在哮喘患者中，气道对深吸气的正常扩张反应不存在或相反（即收缩）。这种功能差异可能是由于气道平滑肌特性的改变或周围肺实质的解耦或减弱所致。最近的研究强调了实质的重要性，甚至假设其不能扩张气道是哮喘的主要病理。虽然现在公认的是，在激动剂刺激下，薄壁组织很容易变硬，但很少有实验证据能够预测其对气道大小的影响。本项目将测试两个主要假设，以评估气道和实质硬化对气道对肺膨胀反应的相对重要性。首先是肺实质收缩增强了肺膨胀对气道大小的影响。二是炎症降低了实质收缩之间这种相互作用的有效性。第二，炎症降低了收缩实质和气道之间相互作用的有效性。为了解决这些假设，我们设计了一系列创新的实验，使用CT成像和新颖的体内挑战来测量肺部膨胀和短暂深度吸气后收缩的气道是如何扩张的。首先，我们将通过测量气道大小（面积）和肺体积随肺压逐步升高和降低的变化来量化收缩气道和肺实质的硬度。我们也将根据一个深刻的启示来衡量这些变化。这些测量将在通气肺的气道和在没有潮汐应力的不同静态肺容量的肺中进行。在另一系列的实验中，我们将确定周围肺实质的收缩如何随着肺扩张影响单个气道的扩张。最后，我们将研究气道炎症改变收缩气道和实质之间相互作用的具体机制。炎症可通过结构效应（水肿和壁增厚）或化学效应（平滑肌反应性炎症细胞改变）影响这种相互作用。我们独特的实验方法不仅允许我们在控制的肺体积下直接测量气道尺寸，而且还允许分离激动剂刺激对单个气道，整个气道树或肺实质的影响。这些实验将提供关于气道收缩在其正常体内结构环境中的行为的新信息。这些信息在文献中是不可用的，但如果我们能够解释和评估可能在气道疾病（如哮喘）中起作用的几种机制，这是必不可少的。

The normal dilatory response of airways to a deep inspiration is absent or reversed (i.e., contractile) in asthmatic subjects. This functional difference could result from altered properties of the airway smooth muscle or from an uncoupling or weakening of the surrounding lung parenchyma. Recent investigations have emphasized the importance of the parenchyma, even postulating that its inability to dilate airways is a primary pathology in asthma. Although it is now accepted that parenchyma stiffening readily occurs with agonist stimulation, there is little experimental evidence that would enable one to predict its effect on airway size. This project will test two primary hypotheses that will evaluate the relative importance of airway and parenchymal stiffening on the airway response to lung inflation. The first is that the effect of lung inflation on airway size is augmented by parenchymal contraction. The second is that inflammation decreases the effectiveness of this interactions between contracted parenchymal contraction. The second is that inflammation decreases the effectiveness of this interaction between contracted parenchyma and airways. To address these hypotheses we have designed an innovative series of experiments using CT imaging and novel in vivo challenges to measure how contracted airways distend with lung inflation and following a transient deep inspiration. First we will quantify the stiffness of contracted airways and lung parenchyma by measuring the airway size (area) and lung volume changes with stepwise increases and decreases in transpulmonary pressure. We will also measure these changes following a deep inspiration. These measurements will be made in airways of ventilated lungs and in lungs held at different static lung volumes without tidal stresses . In another series of experiments we will determine how contraction of the surrounding lung parenchyma affects the dilation individual airways with lung expansion. Finally we will investigate specific mechanisms by which airway inflammation can alter this interaction between the contracted airways and parenchyma. Inflammation can affect this interaction through structural effects (edema and wall thickening) or chemical effects (inflammatory cell alteration of smooth muscle responsiveness). Our unique experimental approach not only allows us to directly measure airway dimensions at controlled lung volumes, but also allows separation of the effects of agonist stimulation on individual airways, the entire airway tree, or the lung parenchyma. These experiments will provide new information about the behavior of contracted airways in their normal in vivo structural environment. This information is not available in the literature, but it is essential if we are to be able to interpret and evaluate several mechanisms that might be operative in airway diseases such as asthma.