Abstract
Background and ObjectivesTissue remodeling is believed to cause recalcitrant chronic rhinosinusitis (CRS). Epithelial-mesenchymal transition (EMT) is a novel clinical therapeutic target in many chronic airway diseases related with tissue remodeling. The aim of this study was to investigate the effect of trichostatin A (TSA) on transforming growth factor (TGF)-β1-induced EMT in airway epithelium and nasal tissue.Materials and MethodsA549 cells, primary nasal epithelial cells (PNECs), or inferior nasal turbinate organ culture were exposed to TSA prior to stimulation with TGF-β1. Expression levels of E-cadherin, vimentin, fibronectin, α-smooth muscle actin (SMA), histone deacetylase 2 (HDAC2), and HDAC4 were determined by western blotting and/or immunofluorescent staining. Hyperacetylation of histone H2 and H4 by TSA was measured by western blotting. After siHDAC transfection, the effects of HDAC2 and HDAC4 silencing on expression of E-cadherin, vimentin, fibronectin, α-SMA, HDAC2, and HDAC4 in TGF-β1-induced A549 were determined by RT-PCR and/or western blotting. We assessed the change in migration capacity of A549 cells by using cell migration assay and transwell invasion assay.ResultsTGF-β1 altered mRNA and protein expression levels of EMT markers including E-cadherin, vimentin, fibronectin, α-SMA, slug, and snail in A549 cells. Inhibition and silencing of HDAC2 and HDAC4 by TSA and siRNA enhanced TGF-β1-induced EMT in A549 cells. TSA blocked the effect of TGF-β1 on the migratory ability of A549 cells. In experiments using PNECs and inferior turbinate organ cultures, TSA suppressed expression of EMT markers induced by TGF-β1.ConclusionsWe showed that EMT is induced by TGF-β1 in airway epithelial cells and nasal tissue via activation of HDAC2 and HDAC4, and that inhibition of HDAC2 and HDAC4 by TSA reduces TGF-β1-induced EMT. This observation indicates that histone deacetylase inhibitors such as TSA could be potential candidates for treatment of recalcitrant CRS related with tissue remodeling.
Highlights
Chronic rhinosinusitis (CRS) is an inflammation of the nose and paranasal sinuses characterized by nasal blockage, nasal discharge, and olfactory dysfunction lasting more than 12 weeks [1]
In experiments using primary nasal epithelial cells (PNECs) and inferior turbinate organ cultures, trichostatin A (TSA) suppressed expression of Epithelialmesenchymal transition (EMT) markers induced by transforming growth factor (TGF)-β1
We showed that EMT is induced by TGF-β1 in airway epithelial cells and nasal tissue via activation of histone deacetylase 2 (HDAC2) and HDAC4, and that inhibition of HDAC2 and HDAC4 by TSA reduces TGF-β1-induced EMT
Summary
Chronic rhinosinusitis (CRS) is an inflammation of the nose and paranasal sinuses characterized by nasal blockage, nasal discharge, and olfactory dysfunction lasting more than 12 weeks [1]. Medical treatment options for CRS include oral antibiotics, topical corticosteroids, systemic steroids, and other medications such as antihistamines, mucolytics, and decongestants. It is known that about one-third of the symptoms of CRS are relieved by medical treatment [2]. Endoscopic sinus surgery is considered an option after failure of above medical treatment. The disease persists in one-third of patients one year after surgery [3]. In spite of considerable effort to identify factors related to disease recalcitrance, such factors are still not clearly understood. Tissue remodeling is believed to cause recalcitrant chronic rhinosinusitis (CRS). Epithelialmesenchymal transition (EMT) is a novel clinical therapeutic target in many chronic airway diseases related with tissue remodeling. The aim of this study was to investigate the effect of trichostatin A (TSA) on transforming growth factor (TGF)-β1-induced EMT in airway epithelium and nasal tissue
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