Ck. Billlngton et al., Modulation of human airway smooth muscle proliferation by type 3 phosphodiesterase inhibition, AM J P-LUNG, 20(3), 1999, pp. L412-L419
Citations number
33
Categorie Soggetti
da verificare
Journal title
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Elevation in cell cAMP content can inhibit mitogenic signaling in cultured
human airway smooth muscle (HASM) cells. We studied the effects of the type
3-selective phosphodiesterase inhibitor siguazodan, the type 4-selective p
hosphodiesterase inhibitor rolipram, and the nonselective inhibitor 9-isobu
tyl-1-methylxanthine (IBMX) on proliferation of cultured HASM cells. At con
centrations selective for the type 3 phosphodiesterase isoform, siguazodan
inhibited both [H-3]thymidine incorporation (IC50 2 mu M) and the increase
in cell number (10 mu M; 64% reduction) induced by platelet-derived growth
factor-BE (20 ng/ml). These effects were mimicked by IBMX. At concentration
s selective for type 4 phosphodiesterase inhibition, rolipram was without e
ffect. a 20-min exposure to siguazodan and rolipram did not increase whole
cell cAMP levels. However, in HASM cells transfected with a cAMP-responsive
luciferase reporter (p6CRE/Luc), increases in cAMP-driven luciferase expre
ssion were seen with siguazodan (3.9-fold) and IBMX (16.5-fold). These data
suggest that inhibition of the type 3 phosphodiesterase isoform present in
airway smooth muscle results in inhibition of mitogenic signaling, possibl
y through an increase in cCAMP-driven gene expression.