Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China.
Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China; Department of Emergency Medicine, Jinling Hospital, Southern Medical University, Nanjing, 210002, PR China.
Toxicol Lett. 2020 Oct 15;333:170-183. doi: 10.1016/j.toxlet.2020.08.004. Epub 2020 Aug 11.
Paraquat (PQ) poisoning-induced pulmonary fibrosis always results in fatal harm to patients. Our study aimed to investigate the functions of the Wnt/β-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/β-catenin signaling, as a fibrosis-related pathway, was discovered to be profoundly activated by PQ. The protein levels of Wnt/β-catenin signaling components including MMP-2, β-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/β-catenin signaling pathway. Dickkopf-1 (DKK1), an antagonist of Wnt/β-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, α-smooth muscle actin (α-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/β-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/β-catenin signaling pathway may be investigated further as a potential fibrosis suppressor for pulmonary fibrosis therapy.
百草枯（PQ）中毒性肺纤维化总是导致患者致命伤害。本研究旨在探讨 Wnt/β-连环蛋白通路在 PQ 诱导的肺纤维化中的作用。通过比较有无 PQ 时大鼠肺组织的蛋白质组图谱，发现 Wnt/β-连环蛋白信号通路作为纤维化相关通路被 PQ 强烈激活。Wnt/β-连环蛋白信号通路的蛋白水平包括 MMP-2、β-连环蛋白、Wnt3a、Wnt10b、Cyclin D1 和 WISP1 在 PQ 处理的大鼠肺组织中增加。令人惊讶的是，PQ 通过激活 Wnt/β-连环蛋白信号通路被发现能够促进肺上皮细胞和成纤维细胞向肌成纤维细胞分化。Dickkopf-1（DKK1）是 Wnt/β-连环蛋白信号通路的拮抗剂，可抑制肌成纤维细胞分化，并减轻体内外 PQ 诱导的肺纤维化。检测到成纤维细胞标志物波形蛋白、α-平滑肌肌动蛋白（α-SMA）和胶原 I 的表达水平，发现当 PQ 处理并用额外的 DKK1 处理恢复时，其表达水平增加。总之，这些试验表明 Wnt/β-连环蛋白信号通路在肺上皮细胞和成纤维细胞的分化中起调节作用，与 PQ 相关的肺纤维化的发病机制。抑制 Wnt/β-连环蛋白信号通路可能作为肺纤维化治疗的一种潜在的纤维化抑制剂进一步研究。
