title: Mechanisms altering airway smooth muscle cell Ca+ homeostasis in two asthma models.
abstract: BACKGROUND
  Asthma is characterized by airway remodeling, altered mucus production and airway smooth muscle cell (ASMC) contraction causing extensive airway narrowing. In particular, alterations of ASMC contractility seem to be of crucial importance. The elevation of the cytoplasmic Ca(2+) concentration is a key event leading to ASMC contraction and changes in the agonist-induced Ca(2+) increase in ASMC have been reported in asthma.
  
  
  OBJECTIVE
  The aim of this study was to investigate mechanisms underlying these changes.
  
  
  METHODS
  Murine tracheal smooth muscle cells (MTSMC) from T-bet KO mice and human bronchial smooth muscle cells (HBSMC) incubated with IL-13 and IL-4 served as asthma models. Acetylcholine-induced changes in the cytoplasmic Ca(2+) concentration were recorded using fluorescence microscopy and the expression of Ca(2+) homeostasis regulating proteins was investigated with Western blot analysis.
  
  
  RESULTS
  Acetylcholine-induced Ca(2+) transients were elevated in both asthma models. This correlated with an increased Ca(2+) content of the sarcoplasmic reticulum (SR). In MTSMC from T-bet KO mice, the expression of the SR Ca(2+) buffers calreticulin and calsequestrin was higher compared to wild-type mice. In HBSMC incubated with IL-13 or IL-4, the expression of ryanodine receptors, inositol-3-phosphate receptors and sarcoplasmic/endoplasmic reticulum Ca(2+) ATPases 2 was increased compared to HBSMC without incubation with interleukins. The enlarged acetylcholine-induced Ca(2+) transients could be reversed by blocking inositol-3-phosphate receptors.
  
  
  CONCLUSIONS
  We conclude that in the murine asthma model the SR Ca(2+) buffer capacity is increased, while in the human asthma model the expression of SR Ca(2+) channels is altered. The investigation of the Ca(2+) homeostasis of ASMC has the potential to provide new therapeutical options in asthma.
authors.affiliation: Pneumology, Medizinische Klinik Innenstadt, Ludwig Maximilian University, Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kellner
authors.forename: Juliane
authors.initials: J
authors.lastname: Tantzscher
authors.forename: Hamza
authors.initials: H
authors.lastname: Oelmez
authors.forename: Martin
authors.initials: M
authors.lastname: Edelmann
authors.forename: Rainald
authors.initials: R
authors.lastname: Fischer
authors.forename: Rudolf Maria
authors.initials: RM
authors.lastname: Huber
authors.forename: Albrecht
authors.initials: A
authors.lastname: Bergner
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D037282:Calreticulin / Q000378:metabolism; D002155:Calsequestrin / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014132:Trachea / Q000166:cytology; D000098815:T-bet Transcription Factor
chemical_list: D037282:Calreticulin; D002155:Calsequestrin; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007377:Interleukin-3; D019837:Ryanodine Receptor Calcium Release Channel; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015847:Interleukin-4; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000109:Acetylcholine; D002118:Calcium