College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China; Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China.
College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China.
Toxicol Appl Pharmacol. 2021 May 1;418:115500. doi: 10.1016/j.taap.2021.115500. Epub 2021 Mar 18.
Copper (Cu) is considered as an essential trace element for living organisms. However, over-exposure to Cu can lead to adverse health effects on human and animals. There are limited researches on pulmonary toxicity induced by Cu. Here, we found that copper sulfate (CuSO)-treatment could induce pulmonary fibrosis with Masson staining and up-regulated protein and mRNA expression of Collagen I and α-Smooth Muscle Actin (α-SMA) in mice. Next, the mechanism underlying Cu-induced pulmonary fibrosis was explored, including transforming growth factor-β1 (TGF-β1)-mediated Smad pathway, mitogen-activated protein kinases (MAPKs) pathway and epithelial-mesenchymal transition (EMT). CuSO triggered pulmonary fibrosis by activation of the TGF-β1/Smad pathway, which was accomplished by increasing TGF-β1, p-Smad2 and p-Smad3 protein and mRNA expression levels. Also, up-regulated protein and mRNA expression of p-JNK, p-ERK, and p-p38 demonstrated that CuSO activated MAPKs pathways. Concurrently, EMT was activated by increasing vimentin and N-cadherin while decreasing E-cadherin protein and mRNA expression levels. Altogether, the abovementioned findings indicate that CuSO treatment may induce pulmonary fibrosis through the activation of EMT induced by TGF-β1/Smad pathway and MAPKs pathways, revealing the mechanism Cu-caused pulmonary toxicity.
铜（Cu）被认为是生物体必需的微量元素。然而，铜暴露过度会对人类和动物的健康产生不利影响。目前关于铜引起的肺毒性的研究有限。在这里，我们发现硫酸铜（CuSO）处理可诱导小鼠肺纤维化，Masson 染色和胶原 I 和α-平滑肌肌动蛋白（α-SMA）的蛋白和 mRNA 表达上调。接下来，我们探讨了 Cu 诱导肺纤维化的机制，包括转化生长因子-β1（TGF-β1）介导的 Smad 通路、丝裂原活化蛋白激酶（MAPKs）通路和上皮间质转化（EMT）。CuSO 通过激活 TGF-β1/Smad 通路引发肺纤维化，该通路通过增加 TGF-β1、p-Smad2 和 p-Smad3 蛋白和 mRNA 表达水平来实现。此外，p-JNK、p-ERK 和 p-p38 的蛋白和 mRNA 表达上调表明 CuSO 激活了 MAPKs 通路。同时，EMT 通过增加波形蛋白和 N-钙粘蛋白，同时减少 E-钙粘蛋白蛋白和 mRNA 表达水平而被激活。综上所述，这些发现表明，CuSO 处理可能通过 TGF-β1/Smad 通路和 MAPKs 通路诱导的 EMT 激活诱导肺纤维化，揭示了 Cu 引起的肺毒性的机制。
