While airway constrictor hyperresponsiveness has long been known as a pathophysiological characteristic of asthma, more recent attention has been placed upon another functional abnormality - the inability of deep breathing to reverse bronchoconstriction in asthmatic subjects, as it does in normal individuals. Asthmatic airways appear to respond to the stretch imposed by a deep breath in an elastic fashion, returning to their original, constricted diameter soon after release of the deep inhalation. In marked contrast, normal airways when constricted respond to stretch with much more plastic deformation, retaining their stretched circumference and resulting in deep breathing-induced reversal of bronchoconstriction. Ample evidence indicates that plastic or elastic behavior of a constricted airway has its origin in the parallel mechanical properties of its contracted airway smooth muscle. Our major objective is to identify the molecular mechanisms that regulate the plasticity-elasticity balance of contracted airway smooth muscle. The key premises underlying this proposal are that 1) the normal bronchodilation response to a deep inspiration is a large effect, 2) this response is abrogated in asthma, and 3) if we understood the molecular mechanisms underlying this response and its failure in asthma, then novel interventions could be designed to restore this bronchodilation mechanism in asthmatics, and could represent an important new therapeutic strategy. We have developed a novel model system that facilitates study of the plasticity-elasticity balance of contracted airway smooth muscle, which in we find that the shortening that occurred during isotonic contraction is reversed by the addition of load fluctuations, and that this relengthening happens on two time scales - within a few seconds (""""""""immediate phase"""""""") and over the entire 20 min of force oscillation (""""""""slow phase""""""""); additional studies implicate different signaling pathways and different effector molecules in the regulation of each phase of relengthening. This model system thus reveals that multiple (at least 2) molecular mechanisms determine overall plasticity of contracted airway smooth muscle, and it provides a platform for their separate study. Using this system, we propose two specific aims designed to identify the signaling pathways and effector molecules that regulate two easily discernible contributions to the overall plasticity of contracted airway smooth muscle. We anticipate that understanding these molecular mechanisms may shed light onto potential dysregulation of these pathways in airway smooth muscle in asthma, and so may suggest strategies by which to restore the powerful endogenous protective deep breath-induced bronchodilation that is lost in asthma.
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