Abstract
Epithelial–mesenchymal transition (EMT) plays a crucial role in the development of pulmonary fibrosis. This study aims to investigate the effects of valproic acid (VPA) on EMT in vitro and in vivo. In vitro, EMT was induced by the administration of transforming growth factor-β1 (TGF-β1) in a human alveolar epithelial cell line (A549). The dose effects of VPA (0.1–3 mM) on EMT were subsequently evaluated at different timepoints. VPA (1 mM) was applied prior to the administration of TGF-β1 and the expression of E-cadherin, vimentin, p-Smad2/3 and p-Akt was assessed. In addition, the effects of a TGF-β type I receptor inhibitor (A8301) and PI3K-Akt inhibitor (LY294002) on EMT were evaluated. In vivo, the effects of VPA on bleomycin-induced lung fibrosis were evaluated by assessing variables such as survival rate, body weight and histopathological changes, whilst the expression of E-cadherin and vimentin in lung tissue was also evaluated. A8301 and LY294002 were used to ascertain the cellular signaling pathways involved in this model. The administration of VPA prior to TGF-β1 in A549 cells prevented EMT in both a time- and concentration-dependent manner. Pretreatment with VPA downregulated the expression of both p-Smad2/3 and p-Akt. A8301 administration increased the expression of E-cadherin and reduced the expression of vimentin. LY294002 inhibited Akt phosphorylation induced by TGF-β1 but failed to prevent EMT. Pretreatment with VPA both increased the survival rate and prevented the loss of body weight in mice with pulmonary fibrosis. Interestingly, both VPA and A8301 prevented EMT and facilitated an improvement in lung structure. Overall, pretreatment with VPA attenuated the development of pulmonary fibrosis by inhibiting EMT in mice, which was associated with Smad2/3 deactivation but without Akt cellular signal involvement.This study investigated the effect of valproic acid (VPA) on epithelial–mesenchymal transition (EMT). In vitro, VPA prevents EMT in a time- and concentration-dependent manner. In vivo, pretreatment with VPA attenuates pulmonary fibrosis development through EMT inhibition in mice, which was associated with Smad2/3 deactivation but without Akt signal involvement.
Highlights
Chemotherapy can trigger the development of lung fibrosis in a subset of patients [1, 2]
A549 cells incubated with valproic acid (VPA) (0.1, 0.3, and 1 mM) and transforming growth factor-β1 (TGF-β1) at 10 ng/ml demonstrated no significant change in cell viability (Fig. 1B)
We applied VPA at various timepoints to determine whether VPA inhibited Epithelial–mesenchymal transition (EMT) in a time-dependent manner. 1 mM VPA was administered for 0.5 h or 72 h prior to TGF-β1, and 0.5 h post-TGF-β1 (Fig. 1C)
Summary
Chemotherapy can trigger the development of lung fibrosis in a subset of patients [1, 2]. This type of lung fibrosis is characterized by various pathological hallmarks, including chronic pulmonary epithelial injury and the proliferation and activation of fibroblasts, which subsequently promote myofibroblast formation and extracellular matrix (ECM) accumulation [3]. Repair mechanisms within the lung are activated which attempt to restore lung function. Dysregulation of these processes may result in the initiation of fibrogenesis [4]. Recent studies have demonstrated that fibroblasts originating from bone marrow [5], endothelial [6], and epithelial cells [7] can all be activated to acquire the Pretreatment with valproic acid alleviates pulmonary fibrosis through epithelial–mesenchymal
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