Copper nanoparticles induce early fibrotic changes in the liver via TGF-β/Smad signaling and cause immunosuppressive effects in rats

Abstract

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.

Keywords:

• Copper nanoparticles
• extracellular matrix
• immune response
• oxidative stress
• transforming growth factor-β1

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [NRF-2016R1D1A2B04936124] and Grant from the KRIBB Research Initiative Program, Republic of Korea [KGM2221844].