Metallothionein ameliorates burn sepsis partly via activation of Akt signaling pathway in mice: A randomized animal study

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Abstract

Introduction: Metallothioneins (MTs) are a family of cysteine-rich and low molecular-weight proteins that can regulate metal metabolism and act as antioxidants. Recent studies showed that MTs played a protective role in excessive inflammation and sepsis. However, the role of MTs in burn sepsis remains unclear. This study is designed to investigate the role of MTs in burn sepsis in an experimental mouse model. Methods: MT-I/II knockout (-/-) mice on a C57BL/6 background and their wild-type (WT) littermates were randomly divided into sham burn, burn, burn sepsis, Zn treated and Zn-MT-2 treated groups. Levels of inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Myeloperoxidase (MPO) activity was detected by spectrophotometry. In in vitro study, exogenous MT was added to macrophages that stimulated with serum from burn sepsis mice with or without Akt inhibitor LY294002. The IL-1 β and IL-6 mRNA expression were detected by quantitative real-time polymerase chain reaction. The levels of Akt expression were determined by western blot. Results: Burn sepsis induced significantly elevated levels of inflammatory cytokines in serum and increased inflammatory infiltration in the liver and lung. These effects were more prominent in MT (-/-) mice than in WT mice. Furthermore, exogenous MT-2 inhibited these elevated inflammatory response in both WT and MT (-/-) mice. MT-2 up-regulated Akt phosphorylation and abrogated the increase of IL-1β and IL-6 mRNA expression from macrophages that stimulated with burn sepsis serum. These effects of MT-2 were abolished in the presence of LY294002. Conclusion: MT-2 ameliorates burn sepsis by attenuating inflammatory response and diminishing inflammatory organ damage, which is at least partly mediated by activation of Akt signaling pathway.

Figures

  • Fig. 1 IL-1β, IL-6, TNF-α, and MCP-1 levels in serum of WT and MT (−/−) mice were detected by ELISA. Data were presented as means ± SD, n = 10 mice/group, *p < 0.01, #p < 0.05
  • Fig. 2 MPO activities in liver and lung of WT and MT (−/−) mice were detected by spectrophotometry. Data were presented as means ± SD, n = 10 mice/group, *p < 0.01
  • Fig. 3 The mRNA expression of ICAM-1 and VCAM-1 in liver and lung of WT and MT (−/−) mice were detected by quantitative real-time PCR. Data were calculated using the 2-ΔΔCt method, where Ct is cycle threshold. n = 10 mice/group, *p < 0.01
  • Fig. 4 IL-1β (a) and IL-6 (b) mRNA expression in cell lysates were detected by quantitative real-time PCR. Data were calculated using the 2-ΔΔCt method, where Ct is cycle threshold. c The protein levels of pAkt and Akt were determined by western blot. Data were presented as means ± SD. Results are representative of at least three independent experiments. *p < 0.01

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Luo, K., Long, H., Xu, B., & Luo, Y. (2015). Metallothionein ameliorates burn sepsis partly via activation of Akt signaling pathway in mice: A randomized animal study. World Journal of Emergency Surgery, 10(1). https://doi.org/10.1186/s13017-015-0044-3

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