title: Sulindac has strong antifibrotic effects by suppressing STAT3-related miR-21.
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.
authors.affiliation: Department 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.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhou
authors.forename: You-Jie
authors.initials: YJ
authors.lastname: Li
authors.forename: Shu-Yan
authors.initials: SY
authors.lastname: Gao
authors.forename: Xiao-Zhi
authors.initials: XZ
authors.lastname: Wang
authors.forename: Ping-Yu
authors.initials: PY
authors.lastname: Wang
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Yan
authors.forename: Shu-Yang
authors.initials: SY
authors.lastname: Xie
authors.forename: Chang-Jun
authors.initials: CJ
authors.lastname: Lv
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001761:Bleomycin; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D008856:Microscopy, Fluorescence; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013467:Sulindac / Q000494:pharmacology*
chemical_list: D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001761:Bleomycin; D015820:Cadherins; D007371:Interferon-gamma; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; D013467:Sulindac; C494088:Stat3 protein, rat; C546082:mirn21 microRNA, rat; C498862:Acta2 protein, rat
keywords: IFN-γ; STAT3; epithelial mesenchymal transition; miRNA; pulmonary fibrosis; sulindac