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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Ortega, Hector
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
Schools of Medicine
United States
Zip Code
Sanderson, Michael J; Bai, Yan; Perez-Zoghbi, Jose (2010) Ca(2+) oscillations regulate contraction of intrapulmonary smooth muscle cells. Adv Exp Med Biol 661:77-96
Delmotte, Philippe; Sanderson, Michael J (2010) Effects of formoterol on contraction and Ca2+ signaling of mouse airway smooth muscle cells. Am J Respir Cell Mol Biol 42:373-81
Ressmeyer, Anna-Rebekka; Bai, Yan; Delmotte, Philippe et al. (2010) Human airway contraction and formoterol-induced relaxation is determined by Ca2+ oscillations and Ca2+ sensitivity. Am J Respir Cell Mol Biol 43:179-91
Perez-Zoghbi, Jose F; Bai, Yan; Sanderson, Michael J (2010) Nitric oxide induces airway smooth muscle cell relaxation by decreasing the frequency of agonist-induced Ca2+ oscillations. J Gen Physiol 135:247-59
Delmotte, Philippe; Ressmeyer, Anna-Rebekka; Bai, Yan et al. (2010) Mechanisms of airway smooth muscle relaxation induced by beta2-adrenergic agonists. Front Biosci (Landmark Ed) 15:750-64
Bai, Yan; Sanderson, Michael J (2009) The contribution of Ca2+ signaling and Ca2+ sensitivity to the regulation of airway smooth muscle contraction is different in rats and mice. Am J Physiol Lung Cell Mol Physiol 296:L947-58
Perez-Zoghbi, Jose F; Karner, Charlotta; Ito, Satoru et al. (2009) Ion channel regulation of intracellular calcium and airway smooth muscle function. Pulm Pharmacol Ther 22:388-97
Lechtreck, Karl-Ferdinand; Sanderson, Michael J; Witman, George B (2009) High-speed digital imaging of ependymal cilia in the murine brain. Methods Cell Biol 91:255-64
Bai, Yan; Edelmann, Martin; Sanderson, Michael J (2009) The contribution of inositol 1,4,5-trisphosphate and ryanodine receptors to agonist-induced Ca(2+) signaling of airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 297:L347-61
Lorenzo, Ivan M; Liedtke, Wolfgang; Sanderson, Michael J et al. (2008) TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells. Proc Natl Acad Sci U S A 105:12611-6

Showing the most recent 10 out of 19 publications