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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071930-03
Application #
6938623
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Banks-Schlegel, Susan P
Project Start
2003-09-01
Project End
2008-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2005
Total Cost
$318,000
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Physiology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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

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