Mucociliary clearance is the primary lung defense mechanism that prevents the accumulation of foreign material in the airways and relies on cooperative ciliary activity. In airway epithelial cells, Ca2+ commonly serves as a signal for cell regulation and strongly influences ciliary beat frequency (CBF). However, our understanding of the regulation and coordination of airway ciliary activity by Ca2+ is extremely poor even though this is vital to our comprehension of the physiology and dysfunction of the airway epithelium in obstructive lung disease. Changes in intracellular Ca2+ concentration occur in the form of propagating intercellular Ca2+ waves or asynchronous Ca2+ oscillations. These signals can encode spatial and temporal regulatory information but the mechanisms underlying Ca2+ oscillations and waves in airway cells, their interactions with each other and the consequences each have for airway cell physiology is virtually unknown. Extracellular ATP stimulates both Ca2+ oscillations and increases in CBF in airway epithelial cells. This is extremely important because ATP (or UTP) is released by the airway epitheliurn and may serve as a local regulator of mucociliary transport. However, the mechanism of ATP release is unknown. Consequently, our hypothesis is that Ca2+ oscillations provide temporal-spatial Ca2+ gradients within individual cells to regulate and coordinate ciliary activity and thereby control mucociliary clearance. To test this hypothesis, our specific aims are 1) to determine the molecular mechanisms linking changes in Ca2+ with changes in CBF in airway epithelial cells and the route of ATP release, 2) to characterize the spatial organization of intracellular Ca2+ oscillations and their relevance to ciliary activity of airway epithelial cells and 3) to quantify the relationship between Ca2+, CBF, metachrony and the control of mucociliary transport. By understanding how Ca2+ signals control and coordinate ciliary activity and how intracellular Ca2+ oscillations occur within cells, this research will significantly contribute to our knowledge and understanding of the pathophysiology of airway defense mechanisms, the principles of Ca2+ signal transduction in non-excitable cells and the potential use of ATP or UTP as therapeutic agents for airway disease.
| Delmotte, Philippe; Sanderson, Michael J (2006) Ciliary beat frequency is maintained at a maximal rate in the small airways of mouse lung slices. Am J Respir Cell Mol Biol 35:110-7 |
| 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 |
| Zhang, Luo; Sanderson, Michael J (2003) The role of cGMP in the regulation of rabbit airway ciliary beat frequency. J Physiol 551:765-76 |
