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Long acting β2-agonist's activation of cyclic AMP cannot halt ongoing mitogenic stimulation in airway smooth muscle cells.

Authors :
Qi Y
Fang L
Stolz D
Tamm M
Roth M
Source :
Pulmonary pharmacology & therapeutics [Pulm Pharmacol Ther] 2019 Jun; Vol. 56, pp. 20-28. Date of Electronic Publication: 2019 Mar 12.
Publication Year :
2019

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 <superscript>(Waf1/Cip1)</superscript> , p27 <superscript>(Kip1)</superscript> , 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 <superscript>(Waf1/Cip1)</superscript> and p27 <superscript>(Kip1)</superscript> 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.<br /> (Copyright © 2019. Published by Elsevier Ltd.)

Details

Language :
English
ISSN :
1522-9629
Volume :
56
Database :
MEDLINE
Journal :
Pulmonary pharmacology & therapeutics
Publication Type :
Academic Journal
Accession number :
30876906
Full Text :
https://doi.org/10.1016/j.pupt.2019.03.005