Changes in airway tone which occur in response to changes in lung volume play a significant role in the regulation of airway caliber. In previous studies, we have demonstrated that many of the effects of lung volume history on airway tone can be attributed to the hysteretic properties of the airway smooth muscle itself. In addition, the mechanisms underlying airway hysteresis appear to be caused primarily by active contractile properties of the muscle. Some of these properties are affected by the level of activation of the muscle and may be altered by factors which affect intracellular Ca2+ homeostasis. The objectives of the proposed experiments are to determine the cellular mechanisms underlying airway hysteresis, and to evaluate how they are affected by modifications in Ca2+ homeostasis. To accomplish this goal we will investigate the mechanisms by which the contraction of airway smooth muscle is affected by muscle length and length history. We will also investigate the mechanisms by which intracellular Ca2+ is regulated in airway muscle, as these processes may ultimately determine the nature of the mechanical responses of the tissue. A number of different techniques and approaches will be employed to accomplish these objectives. Measurements of shortening velocity and of muscle stiffness will be used to evaluate the effects of length history on crossbridge properties. The effects of changes in muscle length or load on the intracellular Ca2+ concentration will be determined using the intracellular Ca2+ indicator, acequorin. Skinned muscles will be used to assess the effects of Ca2+ activation. The mechanisms underlying Ca2+ homeostasis will be evaluated using aequorin, electrophysiologic measurements, and pharmacologic interventions. The results of these studies should provide a better understanding of the mechanisms responsible for airway hysteresis, and enable factors important to the modification of airway hysteretic properties to be assessed. Numerous studies have demonstrated an abnormal hysteresis of the airways of asthmatics, apparently caused by abnormalities in the properties of their airway smooth muscle. These studies could therefore provide a basis for a better understanding of mechanisms of asthma.
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