Related Experiment Videos
Long acting β2-agonist's activation of cyclic AMP cannot halt ongoing mitogenic stimulation in airway smooth muscle
Ying Qi1, Lei Fang2, Daiana Stolz2
1Pulmonary Cell Research and Pneumology, Department Biomedicine & Internal Medicine, University & University Hospital Basel, Petersgraben 4, CH-4031, Basel, Switzerland; Department of Medicine and Division of Pulmonary and Critical Care Medicine, Jishuitan Hospital, Fourth Medical College of Peking Medical University, No 31, Xinjiekou East Street, Xicheng District, Beijing, China.
Abstract:
Airway smooth muscle cell (ASMC) hyperplasia causes airway wall remodelling, which is resisting to therapy. Long acting β2-agonists (LABA) relax airway muscles, but their effect on remodelling is unclear. This study compared the anti-proliferative effect of LABA in human primary ASMC, in situations where LABA were applied before, together, or after platelet derived growth factor (PDGF-BB). Cells obtained from controls (n = 5), and asthma patients (n = 5) were stimulated by PDGF-BB (10 ng/ml) before or after the application of formoterol or salmeterol. Proliferation was determined by direct cell counts over three days, cell cycle control proteins p21(Waf1/Cip1), p27(Kip1), signalling proteins Erk1/2 and p38 mitogen activated protein kinase (MAPK) were detected by immuno-blotting. PDGF-BB induced proliferation was significantly stronger in asthmatic ASMC versus controls. Proliferation was prevented by 30 min pre-incubation with LABA. When LABA were applied together or after PDGF-BB, their anti-proliferative effect was no longer significant. In untreated ASMC, LABA increased the expression of p21(Waf1/Cip1) and p27(Kip1) through cAMP, and this mechanism was abolished by the presence of PDGF-BB. The data show that the anti-proliferative effect of cAMP signalling cannot overcome the mitogenic signalling cascade once it was activated. Therefore, remodelling in asthma cannot be reduced by LABA.