In the classical theory of airway lumen narrowing in asthma, active force in airway smooth muscle is presumed to be in static mechanical equilibrium with the external load against which the muscle has shortened. This theory is useful because it identifies the static equilibrium toward which activated airway smooth muscle would tend if given enough time. The corresponding contractile state toward which myosin-actin interactions would tend is called the latch state. But are the concepts of a static mechanical equilibrium and the latch state applicable in the setting of tidal loading, as occurs during breathing? The investigator's hypothesis is that tidal fluctuations in muscle load cause an excess in the rate of bridge detachment compared with static conditions. These stretched-induced detachment events can come so fast compared with the rate of attachment that the latch state is never attained. Therefore, the interactions of myosin with actin are at every instant tending toward the latch state, but tidal changes in muscle load can come so fast that static equilibrium conditions in the latch state are never attained. This hypothesis leads to specific testable predictions. First, it predicts that contracted airway smooth muscle subjected to small tidal stretches can be maintained in steady dynamically-determined states that are far from static conditions in the latch state. Second, it predicts the existence of a dynamic muscle instability. Third, it predicts that these phenomena are caused by a direct effect of stretch on bridge dynamics. Fourth, it predicts that allergen sensitization changes muscle stability. The proposed research combines measurements of the contractile state with mathematical analysis of the cross bridge mechanisms. The experimental method is to measure the mechanical, biochemical, and metabolic properties that characterize the contractile state of isolated tissues during tidal loading. The analysis addresses the relationship between tissue-level unstable behavior and strain-dependence of the myosin state. The investigators have collected preliminary data that support three of the four testable predictions. The global hypothesis to be tested may be important because it leads to the idea that airway luminal caliber in the healthy lung during bronchoprovocation is probably governed by a dynamic process rather than by a balance of static forces, as is currently believed, and because it shows that failure of airway smooth muscle to escape static equilibrium conditions and the latch state may be a major mechanism contributing to excessive narrowing of the airway lumen in asthma.
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