Air flow in the lungs depends on the maintenance of unobstructed airways and this is a major responsibility of the airway epithelial cells. These cells perform muco-ciliary clearance and ion transport to expel inhaled contaminants and prevent surface dehydration. Abnormalities in these airway defense mechanisms lead to decreased airway caliber. For example, compromised mucociliary clearance leads to chronic obstructive lung disease and defective ion transport is characteristic of cystic fibrosis. Another factor regulating air flow is bronchiole caliber and this is influenced by the contractile state and mass of the airway smooth muscle cells (SMCs). A decrease in airway caliber occurs in asthmatic patients due to airway hyper-reactivity and increased SMC mass. These epithelial functions require multicellular activity and are strongly influenced by changes in intracellular calcium concentration ([Ca2+]i). The location and close apposition of epithelial cells to small bronchiole SMCs also suggests that the epithelial cells may detect lumenal stimuli and pass information to the SMCs. Contraction of SMCs is initiated by an increase in (Ca2+]i but, at the tissue level, force production requires the cooperative effort of multiple cells. This cooperation is not mediated by neuronal activity as all airway SMCs are not innervated and the mechanisms coordinating multicellular increases in [Ca2+]i in SMCs are not understood. In airway epithelial cells, slow propagating increases in [Ca2+]i or intercellular Ca2+ waves are mediated by the diffusion of IP3 through gap junctions. We have recently observed that intercellular Ca2+ waves also occur in airway SMCs and between airway epithelial cells and SMCs. As a result, we hypothesize that heterotypic intercellular Ca2+ signaling provides a direct mechanism by which airway epithelial cells can communicate with airway smooth muscle cells. However, the spatial organization of intercellular Ca2+ waves and how these relate to a physiological action still remain poorly understood. Consequently, our aims are: 1) to characterize the properties, messengers and function of intercellular Ca2+ waves between epithelial and SMCs with digital fluorescence microscopy, in tissue cultures and intact tissue, 2) to determine the relationship between the Ca2+ signaling elements of the cell and the three-dimensional organization of Ca2 + waves in airway epithelial and SMCs and 3,) to identify the physiological role of Ca2+ waves in ciliary activity, cell migration and cell contraction of airway epithelial and SMCs. In summary, our overall objective is to understand the mechanisms and function of intercellular Ca2+ signaling between airway cells. With this understanding our ability to design therapies to counter obstructive lung disease and prevent asthmatic attacks will be enhanced.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Lung Biology and Pathology Study Section (LBPA)
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Banks-Schlegel, Susan P
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University of Massachusetts Medical School Worcester
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