[Ca2+-signaling in smooth muscles cells of the airways in T-bet knock-out mice].
BACKGROUND
Airway smooth muscle cells (ASMC) play a key role in bronchial hyperresponsiveness (BHR). A major component of the signalling cascade leading to ASMC contraction is calcium. T-bet knock-out (KO) mice show the key features of allergic asthma such as a shift towards T (H2)-lymphocytes and display a broad spectrum of asthma-like histological and functional characteristics. In this study, we aimed at investigating whether Ca (2+)-homeostasis of ASMC is altered in T-bet KO-mice as an experimental model of asthma.


METHODS
Lung slices of 100 to 200 microm thickness were obtained from T-bet KO- and wild-type mice. Airway contractions in response to acetylcholine (ACH) were measured by video-microscopy and Ca (2+)-signaling in single ASMC of lung slices was assessed using two-photon microscopy.


RESULTS
Airways from T-bet KO-mice showed increased baseline airway tone (BAT) and BHR compared to those of wild-type mice. The increased BAT was correlated with an increased incidence of spontaneous changes in intracellular Ca (2+)-concentrations, whereas BHR correlated with higher ACH-induced Ca (2+)-transients and an increased proportion of ASMC showing Ca (2+)-oscillations. Emptying intracellular Ca (2+)-stores using caffeine or cyclopiazonic acid induced higher Ca (2+)-elevations in ASMC from T-bet KO compared to wild-type mice.


CONCLUSIONS
Altered Ca (2+)-homeostasis of ASMC contributes to increased BAT and BHR in lung slices from T-bet KO mice as a murine asthma model. We propose that a higher Ca (2+)-content of the intracellular Ca (2+)-stores is involved in the pathophysiology of these changes.
Bergner
A
A
Pneumologie, Medizinische Klinik-Innenstadt der Ludwig-Maximilians Universität München, Germany. albrecht.bergner@med.uni-muenchen.de
Kellner
J
J
Gamarra
F
F
Huber
R M
RM
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics*; D002118:Calcium / Q000502:physiology*; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000502:physiology* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000172:deficiency* / Q000235:genetics*; D000098815:T-bet Transcription Factor
D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D002118:Calcium