INFLAMMATORY ALTERATIONS ON AIRWAY MECHANICS IN VIVO

哮喘患者对深吸气的正常呼吸道舒缩反应缺失或反转(即收缩)。这种功能差异可能是由于气道平滑肌属性的改变或周围肺实质的解偶联或减弱所致。最近的研究强调了实质的重要性，甚至假设它无法扩张呼吸道是哮喘的主要病理。虽然现在公认的是，激动剂刺激很容易发生实质僵硬，但几乎没有实验证据能够预测其对呼吸道大小的影响。这个项目将测试两个主要假设，它们将评估气道和实质僵硬对气道对肺充气的反应的相对重要性。首先，肺充气对气道大小的影响因实质收缩而增大。第二，炎症降低了收缩的实质收缩之间相互作用的有效性。第二，炎症降低了收缩的实质和呼吸道之间的这种相互作用的有效性。为了解决这些假设，我们设计了一系列创新的实验，使用CT成像和新颖的活体挑战来测量收缩的呼吸道如何随着肺充气和短暂的深度吸气而扩张。首先，我们将通过测量气道大小(面积)和肺体积的变化来量化收缩的气道和肺实质的僵硬程度，这些变化随着经肺压力的逐步增加和减少而变化。我们还将在深刻的灵感之后衡量这些变化。这些测量将在呼吸机肺的呼吸道中进行，并在不同静态肺容量而没有潮汐压力的肺中进行。在另一系列实验中，我们将确定周围肺实质的收缩如何影响肺扩张的单个气道的扩张。最后，我们将研究呼吸道炎症改变收缩的呼吸道和实质之间的这种相互作用的具体机制。炎症可以通过结构效应(水肿和管壁增厚)或化学效应(炎症细胞改变平滑肌反应性)影响这种相互作用。我们独特的实验方法不仅允许我们在受控肺容量下直接测量呼吸道尺寸，而且还允许分离激动剂刺激对单个气道、整个呼吸道树或肺实质的影响。这些实验将提供有关收缩的呼吸道在其正常的活体结构环境中的行为的新信息。文献中没有这些信息，但如果我们能够解释和评估几种可能对哮喘等呼吸道疾病起作用的机制，这些信息是必不可少的。

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.