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 parenchymal stiffening readily occurs with agonist stimulation, there is little experimental evidence that would enable one to predict its effect on airway size. This proposal 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 interaction between contracted parenchyma and airways. To address these hypotheses the investigators 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 they 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. They 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 they will determine how contraction of the surrounding lung parenchyma affects the dilation individual airways with lung expansion. Finally they will investigate specific mechanisms by which airway inflammation can alter this interaction between the contracted airways and parenchyma. These experiments will provide new information about the behavior of contracted airways in their normal in vivo structural environment. This is new information that is essential for the interpretation and evaluation several mechanisms that might be operative in airway diseases such as asthma.
