The overall goal of this project is to further our understanding of the mechanisms which govern the regulation of airway smooth muscle tone under the dynamic conditions present during breathing. The responses of airway smooth muscle to contractile stimuli are determined not only by the intracellular signalling pathways initiated by those stimuli, but also by the mechanical environment of the muscle. Dynamic changes in muscle length and load such as occur during breathing profoundly influence airway tone. Airway smooth muscle is unique among smooth muscle tissues in that it is constantly subjected to large mechanical perturbations which modulate its responses to contractile stimuli. Thus simple measurements of isometric force are not adequate to fully,evaluate the potential effects of pharmacologic agents on airway tone. The response of airway smooth muscle to changes in its mechanical environment are determined primarily by the kinetic properties of crossbridges. Crossbridge behavior in smooth muscle tissues is modulated by multiple second messengers which affect contractile protein activity. Agonists which activate different second messenger pathways may have distinct modulatory effects on contractile proteins, and therefore have different effects on the kinetic behavior of crossbridges. The proposed studies are based on the hypothesis that differences in the effects of various agonists and hormones on crossbridge kinetics will modify the response of airway smooth muscle to mechanical perturbations. The initial objective of the proposed studies will be to determine how diverse pharmacologic mechanisms for activating canine airway smooth muscles affect force generation and shortening velocity, and to determine how these mechanical properties relate to intracellular Ca+, contractile protein phosphorylation, and the production of second messengers. A second objective will be to determine how the behavior of the muscle during mechanical perturbations such as step changes in length or load, or continuous lengthening or shortening, is affected by diverse pharmacologic stimuli. Studies will investigate how these mechanical perturbations affect the contribution of attached crossbridges to the generation of active force, and how muscle length and length history affect intracellular Ca2+ and contractile protein phosphorylation in response to various stimuli. A final goal of these studies will be to determine how pharmacologic stimuli with different mechanisms of activation affect the mechanical properties of isolated bronchial segments under dynamic conditions. Patients with pathological conditions such as asthma or bronchitis exhibit abnormalities in the response of the airways to changes in lung volume. Thus a fuller understanding of the intracellular mechanisms which control the behavior of airway smooth muscle under dynamic conditions may contribute to our understanding of obstructive airway disease.
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