Copper nanoparticles (Cu NPs) have various uses, including as additives in polymers/plastics, lubricants for metallic coating, and biomedical applications. We investigated the role of transforming growth factor (TGF)-β1 signaling in hepatic damage caused by Cu NPs and explored the effects of a 28-day repeated oral administration to Cu NPs on the immune response. The exposure to Cu NPs caused a dose-dependent increase in Cu levels in the liver and spleen. Cu NPs caused hepatic damage and markedly increased oxidative stress in liver tissues. Cu NPs induced activation of TGF-β1/Smad signaling by induction of vascular endothelial growth factor and matrix metalloproteinase-9. Exposure to Cu NPs also induced activation of Smad-independent pathways, phosphorylation of mitogen-activated protein kinases (MAPKs) and Akt/FoxO3. Consistent with the activation of TGF-β1/Smad-dependent and -independent pathways, Cu NPs markedly increased the deposition and induction of extracellular matrix components, α-smooth muscle actin, and collagens in liver tissues. In addition, repeated exposure to Cu NPs suppressed the proliferation of mitogenically stimulated T- or B-lymphocytes and decreased CD3⁺ (particularly, CD3⁺CD4⁺CD8⁻) and CD45⁺ population, followed by decreased levels of immunoglobulins and Th1/Th2 type cytokines. Collectively, Cu NPs caused hepatic damage and induced pro-fibrotic changes, which were closely related to the activation of oxidative stress-mediated TGF-β1/Smad-dependent and -independent pathways (MAPKs and Akt/FoxO3). We confirmed the immunosuppressive effect of Cu NPs via the inhibition of mitogen-stimulated spleen-derived lymphocyte proliferation and suppression of B- or T-lymphocyte-mediated immune responses.

中文翻译：

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铜纳米颗粒通过TGF- β / Smad信号传导诱导肝脏早期纤维化改变，并在大鼠中产生免疫抑制作用

铜纳米颗粒（Cu NPs）具有多种用途，包括作为聚合物/塑料中的添加剂，金属涂层的润滑剂和生物医学应用。我们研究了转化生长因子（TGF）-β1信号在铜纳米颗粒引起的肝损伤中的作用，并探讨了重复口服28天对铜纳米颗粒的免疫反应的影响。暴露于铜纳米颗粒会导致肝脏和脾脏中铜的含量呈剂量依赖性增加。Cu NPs引起肝损伤并显着增加肝组织中的氧化应激。Cu NPs通过诱导血管内皮生长因子和基质金属蛋白酶9诱导TGF-β1/ Smad信号的激活。暴露于铜纳米颗粒还会诱导Smad依赖性途径的激活，丝裂原激活的蛋白激酶（MAPK）和Akt / FoxO3的磷酸化。与TGF-β1/ Smad依赖性和非依赖性途径的激活相一致，Cu NPs明显增加了肝组织中细胞外基质成分，α-平滑肌肌动蛋白和胶原蛋白的沉积和诱导。此外，反复暴露于铜纳米颗粒会抑制有丝分裂刺激的T或B淋巴细胞的增殖，并降低CD3⁺（特别是，CD3 ⁺ CD4 ⁺ CD8 ^- ）和CD45 ⁺群体，随后的免疫球蛋白及Th1 / Th2型细胞因子水平的降低。Cu NPs共同引起肝损伤并诱导纤维化改变，这与氧化应激介导的TGF-β1/ Smad依赖性和非依赖性途径（MAPK和Akt / FoxO3）的激活密切相关。我们通过抑制有丝分裂原刺激的脾源性淋巴细胞增殖和抑制B或T淋巴细胞介导的免疫反应，证实了Cu NPs的免疫抑制作用。