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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049288-09
Application #
6526821
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Banks-Schlegel, Susan P
Project Start
1993-12-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2004-08-31
Support Year
9
Fiscal Year
2002
Total Cost
$324,241
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Physiology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Zhang, Luo; Han, Demin; Sanderson, Michael J (2005) Effect of isoproterenol on the regulation of rabbit airway ciliary beat frequency measured with high-speed digital and fluorescence microscopy. Ann Otol Rhinol Laryngol 114:399-403
Bergner, Albrecht; Sanderson, Michael J (2003) Airway contractility and smooth muscle Ca(2+) signaling in lung slices from different mouse strains. J Appl Physiol 95:1325-32; discussion 1314
Zhang, Luo; Sanderson, Michael J (2003) Oscillations in ciliary beat frequency and intracellular calcium concentration in rabbit tracheal epithelial cells induced by ATP. J Physiol 546:733-49
Zhang, Luo; Sanderson, Michael J (2003) The role of cGMP in the regulation of rabbit airway ciliary beat frequency. J Physiol 551:765-76
Bergner, Albrecht; Sanderson, Michael J (2002) ATP stimulates Ca2+ oscillations and contraction in airway smooth muscle cells of mouse lung slices. Am J Physiol Lung Cell Mol Physiol 283:L1271-9
Bergner, Albrecht; Sanderson, Michael J (2002) Acetylcholine-induced calcium signaling and contraction of airway smooth muscle cells in lung slices. J Gen Physiol 119:187-98
Fry, T; Evans, J H; Sanderson, M J (2001) Propagation of intercellular calcium waves in C6 glioma cells transfected with connexins 43 or 32. Microsc Res Tech 52:289-300
Braet, K; Paemeleire, K; D'Herde, K et al. (2001) Astrocyte-endothelial cell calcium signals conveyed by two signalling pathways. Eur J Neurosci 13:79-91
Leybaert, L; Sanderson, M J (2001) Intercellular calcium signaling and flash photolysis of caged compounds. A sensitive method to evaluate gap junctional coupling. Methods Mol Biol 154:407-30
Paemeleire, K; Martin, P E; Coleman, S L et al. (2000) Intercellular calcium waves in HeLa cells expressing GFP-labeled connexin 43, 32, or 26. Mol Biol Cell 11:1815-27

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