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.
Keywords: Asthma; Long acting β(2)-agonists; Remodelling; Smooth muscle cells.
Copyright © 2019. Published by Elsevier Ltd.