TGF-β1-induced EMT activation via both Smad-dependent and MAPK signaling pathways in Cu-induced pulmonary fibrosis

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 (CuSO4)-treatment could induce pulmonary fibrosis with Masson staining and up-regulated protein and mRNA expression of Collagen I and alpha-Smooth Muscle Actin (alpha-SMA) in mice. Next, the mechanism underlying Cu-induced pulmonary fibrosis was explored, including transforming growth factor-beta 1 (TGF-beta 1)-mediated Smad pathway, mitogen-activated protein kinases (MAPKs) pathway and epithelial-mesenchymal transition (EMT). CuSO4 triggered pulmonary fibrosis by activation of the TGF-beta 1/Smad pathway, which was accomplished by increasing TGF-beta 1, 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 CuSO4 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 CuSO4 treatment may induce pulmonary fibrosis through the activation of EMT induced by TGF-beta 1/Smad pathway and MAPKs pathways, revealing the mechanism Cu-caused pulmonary toxicity.

Automated summary

Copper is an essential trace element for living organisms, but over-exposure can lead to adverse health effects. Research found that copper sulfate treatment induced pulmonary fibrosis in mice, activating multiple signaling pathways and causing epithelial-mesenchymal transition. This study reveals the mechanism of copper-induced pulmonary toxicity through EMT induced by TGF-beta 1/Smad and MAPKs pathways.