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Sulindac has strong antifibrotic effects by suppressing STAT3-related miR-21
Xue Zhou1, You-Jie Li, Shu-Yan Gao
1Department of Clinical Medicine, Binzhou Medical University, Yantai, China; Key Laboratory of Tumour Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, China.
Abstract:
Pulmonary fibrosis (PF) is a disease with an unknown cause and a poor prognosis. In this study, we aimed to explore the pathogenesis of PF and the mechanism of sulindac in attenuating bleomycin (BLM)-induced PF. The rat PF model was induced by BLM and verified through histological studies and hydroxyproline assay. The severity of BLM-induced PF in rats and other effects, such as the extent of the wet lung to bw ratios, thickening of alveolar interval or collagen deposition, was obviously ameliorated in sulindac-treated rat lungs compared with BLM-induced lungs. Sulindac also reversed the epithelial mesenchymal transition (EMT) and inhibited the PF process by restoring the levels of E-cadherin and α-smooth muscle actin (SMA) in A549 cells. Our results further demonstrated that the above effects of sulindac might be related to regulating of interferon gamma (IFN-γ) expression, which further affects signal transducers and activators of transcription 3 (STAT3) and phosphorylated STAT3 (p-STAT3) levels. Moreover, higher miR-21 levels with the decreased E-cadherin and increased α-SMA expressions were found in transforming growth factor-β1-treated A549 cells, which can be reversed by sulindac. Collectively, our results demonstrate that by decreasing IFN-γ-induced STAT3/p-STAT3 expression to down-regulate miR-21, sulindac could significantly reverse EMT in A549 cells and prevent BLM-induced PF.
Insights
Sulindac treatment significantly reduced pulmonary fibrosis (PF) in rats by reversing epithelial mesenchymal transition (EMT). This drug may prevent PF by regulating interferon gamma (IFN-γ) and microRNA-21 (miR-21) pathways.
Area of Science:
- Pulmonology
- Pharmacology
- Cell Biology
Background:
- Pulmonary fibrosis (PF) is a progressive lung disease with unknown etiology and poor prognosis.
- Bleomycin (BLM)-induced lung injury is a common model for studying PF pathogenesis.
- Understanding the mechanisms underlying PF and identifying potential therapeutic agents are critical.
Purpose of the Study:
- To investigate the pathogenesis of PF and the protective mechanism of sulindac against BLM-induced PF.
- To explore sulindac's effects on epithelial mesenchymal transition (EMT) and related molecular pathways.
- To elucidate the role of interferon gamma (IFN-γ), STAT3, and miR-21 in sulindac's antifibrotic action.
Main Methods:
- A rat model of PF was established using BLM induction.
- Histological analysis and hydroxyproline assays were performed to assess lung fibrosis.
- A549 cells were used to study the effects of sulindac on EMT, E-cadherin, α-SMA, IFN-γ, STAT3/p-STAT3, and miR-21.
Main Results:
- Sulindac treatment significantly ameliorated BLM-induced PF in rats, reducing lung wet weight to body weight ratios, alveolar thickening, and collagen deposition.
- Sulindac reversed EMT in A549 cells by restoring E-cadherin and decreasing α-SMA expression.
- Sulindac's antifibrotic effects were associated with the regulation of IFN-γ, STAT3/p-STAT3, and miR-21 levels, reversing TGF-β1-induced EMT markers.
Conclusions:
- Sulindac demonstrates significant antifibrotic effects in BLM-induced pulmonary fibrosis.
- Sulindac prevents PF by inhibiting EMT, potentially through the downregulation of IFN-γ-induced STAT3/p-STAT3 signaling and subsequent reduction of miR-21.
- These findings suggest sulindac as a potential therapeutic agent for pulmonary fibrosis.
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