Yang Zhou , Guifang Yang , Jiqiang Liu , Shuo Yao , Jingsi Jia , Xianming Tang , Xun Gong , Fang Wan , Ren Wu , Zhenyu Zhao , Hengxing Liang , Linxia Liu , Qimi Liu , Shanshan Xie , Xian Long , Xudong Xiang , Guyi Wang , Bing Xiao
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引用次数: 0
Abstract
Objective
To investigate the role and underlying mechanism of Methyl-CpG binding domain protein 2 (MBD2) in the pathogenesis of acute respiratory distress syndrome (ARDS)-related pulmonary fibrosis.
Methods
Murine models for ARDS-related pulmonary fibrosis were established in wildtype or MBD2 knockout mice, expressions of MBD2 were determined with immunohistochemistry (IHC), immunofluorescence, and western blot. Epithelial-to-mesenchymal transition (EMT) was detected with determined with decreased expression of E-cadherin and increased expressions of N-cadherin, Vimentin, and α-smooth muscle actin (α-SMA). Transforming growth factor β (TGF-β) treated mouse lung epithelial-12 (MLE-12) cells and primary human type II alveolar epithelial cells were applied to establish in vitro model for EMT. Transcriptional sequencing with RNA-Seq and Chromatin immunoprecipitation (ChIP) assay were used to explore the potential targets of MBD2. Single cell sequencing data and Human pulmonary fibrosis samples were analyzed.
Results
Bleomycin (BLM) and lipopolysaccharide (LPS) induced EMT, pulmonary fibrosis, and increased expression of MBD2 in alveolar epithelial cells of mice, and MBD2 knockout significantly alleviated BLM- and LPS-induced pulmonary fibrosis and EMT. TGF-β induced EMT and elevated MBD2 expressions in alveolar epithelial cells, which was mitigated by MBD2 knockdown and aggravated by MBD2 overexpression. Frizzled 2 (FZD2) was found to be the potential target of MBD2. Single-cell sequencing analysis of ARDS patients suggested elevated expression of MBD2 in alveolar epithelial cells, and MBD2 expression was elevated in the lungs of patients with pulmonary fibrosis.
Conclusion
Our results indicated that MBD2 could promote EMT and ARDS-related pulmonary fibrosis, potentially by modulating the expression of FZD2.
期刊介绍:
BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.