Abstract
Increased airway smooth muscle (ASM) mass is a prominent hallmark of airway remodeling in asthma. Inhaled corticosteroids and long-acting beta2-agonists remain the mainstay of asthma therapy, however are not curative and ineffective in attenuating airway remodeling. The geranyl acetophenone 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA), an in-house synthetic non-steroidal compound, attenuates airway hyperresponsiveness and remodeling in murine models of asthma. The effect of tHGA upon human ASM proliferation, migration and survival in response to growth factors was assessed and its molecular target was determined. Following serum starvation and induction with growth factors, proliferation and migration of human bronchial smooth muscle cells (hBSMCs) treated with tHGA were significantly inhibited without any significant effects upon cell survival. tHGA caused arrest of hBSMC proliferation at the G1 phase of the cell cycle with downregulation of cell cycle proteins, cyclin D1 and diminished degradation of cyclin-dependent kinase inhibitor (CKI), p27Kip1. The inhibitory effect of tHGA was demonstrated to be related to its direct inhibition of AKT phosphorylation, as well as inhibition of JNK and STAT3 signal transduction. Our findings highlight the anti-remodeling potential of this drug lead in chronic airway disease.
Highlights
Airway remodeling, a collective term describing the structural changes in the asthmatic airway, occurs in conjunction with, or as a result of, chronic airway inflammation[1,2]
A similar trend was observed in which induced human bronchial smooth muscle cells (hBSMCs) showed a 10-fold increase in Ki-67 mRNA expression which was significantly inhibited with 20 μM and 10 μM with trihydroxy-3-geranyl acetophenone (tHGA) (Fig. 1c)
Forskolin (10 μM), which served as the positive assay control, significantly reduced growth factor-induced hBSMC proliferation which correlated with reduced Ki-67 mRNA expression
Summary
A collective term describing the structural changes in the asthmatic airway, occurs in conjunction with, or as a result of, chronic airway inflammation[1,2]. This increase in cell number is either due to increased cellular proliferation, reduced apoptosis or/and increased cellular migration towards the airway lumen in response to proinflammatory mediators release[14,15] Proinflammatory mediators such as growth factors and cytokines activate several signal transduction pathways through binding to tyrosine kinase receptor (RTK) and G protein-coupled receptors (GPCRs) that culminate in proliferation and migration of ASM16–19. In this communication, we describe the inhibitory effect of tHGA upon growth factor-induced ASM cell proliferation and migration in an established cellular model. This effect was found to be related to the inhibition of AKT phosphorylation, a downstream signaling molecule of the PI3K pathway that plays a regulatory role in smooth muscle cell proliferation, migration and apoptosis[20,21]
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