Modulation of human airway smooth muscle proliferation by type 3 phosphodiesterase inhibition

Abstract

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 phosphodiesterase inhibitor rolipram, and the nonselective inhibitor 3-isobutyl-1-methylxanthine (IBMX) on proliferation of cultured HASM cells. At concentrations selective for the type 3 phosphodiesterase isoform, siguazodan inhibited both [3H]thymidine incorporation (IC50 2 μM) and the increase in cell number (10 μM; 64% reduction) induced by platelet-derived growth factor-BB (20 ng/ml). These effects were mimicked by IBMX. At concentrations selective for type 4 phosphodiesterase inhibition, rolipram was without effect. 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 expression 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, possibly through an increase in cAMP-driven gene expression.

Blocking of Akt/NF-κB Signaling by Pentoxifylline Inhibits Platelet-Derived Growth Factor–Stimulated Proliferation in Brown Norway Rat Airway Smooth Muscle Cells

“…PTX inhibits phosphodiesterase activity, resulting in an increase in cAMP (18). An increase in cAMP can inhibit proliferation (29). cAMP inhibited the activation of Rap1 and reduced Akt phosphorylation (30).…”

Raf-1 kinase mediates adenylyl cyclase sensitization by TNF-α in human airway smooth muscle cells

“…Tumor necrosis factor (TNF)-␣ is one cytokine implicated in the exacerbation of asthma (3,6,10), and recent clinical studies raise hope that targeted therapy against TNF-␣ may improve asthma symptoms (6). Cyclic AMP is an important second messenger involved in the regulation of the contractile state, proliferation (8,25,34), migration (19), and cytokine secretory abilities (1) of airway smooth muscle cells. Previous studies in human airway smooth muscle cells have shown that cytokines, such as TNF-␣ and IL-1␤, directly influence cellular cAMP levels by "sensitizing" the activities of adenylyl cyclase enzymes (9,29), but the intracellular signaling pathways for the modification of adenylyl cyclase activity are unknown.…”

Bronchial hyperreactivity: pathogenesis and treatment options

“…However, the work presented by Kumara a et al [17] reported that pathogenesis of BHR could be independent on the inflammation and can be present in IL-4 and IL-13 knock-out animals. Inhalation of IL-5 in experiment leads to the increase of the eosinophils and onset of BHR [18]. IL-9 produced by T lymphocytes, eosinophils and mast cells stimulates in turn proliferation of T lymphocytes, increases production of IgE in B lymphocytes and supports proliferation and differentiation of mast cells.…”

“…Another selective inhibitor of PDE3 siguazodan inhibited allergen induced bronchoconstriction in sensitized guinea pigs [48]. The same drug in vitro significantly reduced proliferation of airway smooth muscle [49]. Administration of selective PDE3 inhibitors olprinon [50] and MKS492 [51] induced significant bronchodilatation with minimal systemic side effects.…”