期刊
TOXICOLOGY LETTERS
卷 333, 期 -, 页码 170-183出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2020.08.004
关键词
paraquat poisoning; pulmonary fibrosis; myofibroblast differentiation; epithelial-mesenchymal transition; Wnt/beta-catenin signaling pathway
类别
资金
- National Natural Science Foundation of China [81401583, 81701894]
- Social Development Projects of Jiangsu Province [BE2017720]
- Jiangsu Provincial Medical Youth Talent [QNRC2016909, QNRC2016908]
- Natural Science Foundation of Jiangsu Province [BK20190247]
- China Postdoctoral Science Foundation [2018M643890]
- Jiangsu Postdoctoral Science Foundation [2018K048A]
Paraquat (PQ) poisoning-induced pulmonary fibrosis always results in fatal harm to patients. Our study aimed to investigate the functions of the Wnt/beta-catenin pathway in PQ-induced pulmonary fibrosis. By comparing the proteomic profiles of rat lung tissues using protein array in the absence or presence of PQ, the Wnt/beta-catenin signaling, as a fibrosis-related pathway, was discovered to be profoundly activated by PQ. The protein levels of Wnt/beta-catenin signaling components including MMP-2, beta-catenin, Wnt3a, Wnt10b, Cyclin D1, and WISP1 were increased in PQ-treated rat lung tissues. Surprisingly, PQ was found to be able to promote lung epithelial cells and fibroblasts differentiating into myofibroblasts by activating Wnt/beta-catenin signaling pathway. Dickkopf-1 (DKK1), an antagonist of Wnt/beta-catenin signaling pathway, could inhibit the myofibroblast differentiation and attenuate PQ-induced pulmonary fibrogenesis in vitro and in vivo. The expression levels of fibroblasts markers Vimentin, alpha-smooth muscle actin (alpha-SMA) and Collagen I was detected and found to be increased when PQ treated and restored with additional DKK1 treatment. In summary, these assays indicated that Wnt/beta-catenin signaling pathway played a regulatory role in the differentiation of lung epithelial cells and fibroblasts, and the pathogenesis of pulmonary fibrosis related to PQ. Inhibition of the Wnt/beta-catenin signaling pathway may be investigated further as a potential fibrosis suppressor for pulmonary fibrosis therapy.
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