Inhibition of Wnt/β-catenin signaling suppresses bleomycin-induced pulmonary fibrosis by attenuating the expression of TGF-β1 and FGF-2.
Pulmonary fibrosis is a progressive lung disorder of unknown etiology, which is characterized by alterations in alveolar epithelium function, fibroblast activation, and increased extracellular matrix deposition. Recent studies have demonstrated that PF is associated with uncontrolled production of cytokines after lung injury. In the present study, we found that transforming growth factor-β1 (TGF-β1) and fibroblast growth factor 2 (FGF-2) were both upregulated in bleomycin-induced fibrotic lung tissue and primary murine alveolar epithelial Type II (ATII) cells treated with bleomycin. Furthermore, we discovered that TGF-β1 could induce the differentiation of lung resident mesenchymal stem cells (LR-MSCs) into fibroblasts, which may play an essential role in PF. LR-MSCs incubated with FGF-2 showed modest alterations in the expression of α-SMA and Vimentin. Moreover, in our study, we found that Wnt/β-catenin signaling was activated both in vitro and in vivo as a result of bleomycin treatment. Interestingly, we also found that suppression of the Wnt/β-catenin signaling could significantly attenuate bleomycin-induced PF accompanied with decreased expression of TGF-β1 and FGF-2 in vitro and in vivo. These results support that controlling the aberrant expression of TGF-β1 and FGF-2 via inhibition of Wnt/β-catenin signaling could serve as a potential therapeutic strategy for PF.
Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China. Electronic address: chenxiang910110@163.com.
Xiang
X
Chen
Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China. Electronic address: willscw@live.cn.
Chaowen
C
Shi
Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China. Electronic address: mengxiann@yeah.net.
Xiannan
X
Meng
Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China. Electronic address: szzkj2011@gmail.com.
Kaijia
K
Zhang
Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China. Electronic address: lixiaoyaonju@163.com.
Xiaoyao
X
Li
Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China. Electronic address: wangcongweihai@126.com.
Cong
C
Wang
Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Research Center, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. Electronic address: zou.xiang@gu.se.
Zou
Z
Xiang
Department of Medicine, Division of Nephrology, Penn State University College of Medicine, Hershey, PA 17033, United States. Electronic address: kebinhu@hmc.psu.edu.
Kebin
K
Hu
Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China. Electronic address: hanxd@nju.edu.cn.
Xiaodong
X
Han
D000818:Animals; D001761:Bleomycin; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects
C501127:Dkk1 protein, mouse; D006575:Heterocyclic Compounds, 3-Ring; D036341:Intercellular Signaling Peptides and Proteins; D053773:Transforming Growth Factor beta1; C544261:XAV939; D016222:Fibroblast Growth Factor 2; D001761:Bleomycin
Alveolar epithelial type II cells (ATII cells); Fibroblast growth factor (FGF)-2; Fibroblastic differentiation; Lung resident mesenchymal stem cells (LR-MSCs); Transforming growth factor (TGF)-β1