A characteristic of asthma is airway hyper-reactivity, a response acutely mediated by smooth muscle cell (SMC) contraction. SMC contractility is initiated by increases in intracellular calcium concentration ([Ca2+]i) but the mechanisms of Ca2+ signaling in airway SMCs and how these relate to changes in airway caliber are poorly understood. To address this problem, we have developed a unique lung slice preparation that retains many properties of the lung structure, and in which the Ca2+ signaling of the SMCs and the associated airway contraction or relaxation can be measured simultaneously with confocal microscopy. Our data shows that airway SMCs display a graded range of IP3-based Ca2+ signaling that consists of elemental Ca2+ signals, intracellular Ca2+ oscillations and Ca2+ waves and that these signals correlate with the establishment of resting airway tone as well as the initiation and maintenance of SMC and airway contraction. ? ? Consequently, we hypothesize that the frequency of the Ca2+ signals in SMCs serves to regulate Ca2+ airway caliber. To test this idea, we plan to determine: 1) the Ca signaling mechanisms responsible for the Ca2+ establishment of resting airway tone by investigating the elemental Ca signaling and mechanism of spontaneous Ca2+ oscillations and contractions of airway SMCs, 2) if airway caliber is regulated by frequency-modulation (FM) mediated by Ca2+ oscillations, and 3) how Ca2+ signaling and contraction is altered in airway SMCs of mouse models for hyper-reactivity and asthma. By understanding the graded mechanisms of elemental Ca2+ signaling and Ca2+ oscillations in lung SMCs and how these events regulate SMC contractility and relate to airway caliber, we can gain the necessary insight needed to approach a therapeutic strategy for modulating airway hyper-reactivity.
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