Prophylactic simvastatin treatment modulates the immune response and increases survival of mice following induction of lethal sepsis

Abstract

Objective: To investigate whether and how simvastatin mediates protection from lethal sepsis, using a mouse model.

Methods: Sixty C57BL/6 mice were selected and divided into three groups (“control,” “model,” and “observation”; n = 20 mice per group). Mice in the model and observation groups underwent cecal ligation and puncture; mice in the observation group received simvastatin. After 24 hours of induced sepsis, serum concentrations of IL-6, TNF-α, IL-1, and IL-10 were measured by ELISA. Serum malondialdehyde (MDA) concentrations and serum superoxide dismutase (SOD) activities were quantified by radioimmunoassay.

Results: The mean duration of survival of mice in the observation group was significantly longer than that of the model group. The serum concentrations of IL-6, TNF-α, IL-1, IL-10, and MDA were significantly higher in the observation group than in the control group. Serum SOD activities were significantly lower in the observation group than in the control group.

Conclusions: Simvastatin can alleviate symptoms of sepsis in mice and improve their rates of survival. The mechanism of action of simvastatin may be mediated by inhibition of the systemic inflammatory response and oxidative stress.

Keywords: Sepsis; cecal ligation and puncture; interleukin-1; interleukin-10; interleukin-6; malondialdehyde; oxidative stress; simvastatin; superoxide dismutase; survival rate.

Figure 1.

Effect of simvastatin on the survival rate of mice with sepsis. Survival statuses were examined in the three groups of mice at 7 days after sepsis modeling. Compared with the control group, mice in the model group had significantly shorter mean duration of survival after CLP (P < 0.05). The mean duration of survival of mice in the observation group was longer than that of the model group (P < 0.05). CLP: cecal ligation and puncture. *P < 0.05 compared with the control group, ^#P < 0.05 compared with the model group.

Figure 2.

Impact of simvastatin on clinical scores in mice with sepsis. The three groups of mice were observed and scored. The mean clinical score was higher in the model group than in the control group (P < 0.05), whereas it was significantly lower in the observation group than in the model group (P < 0.05). CLP: cecal ligation and puncture. *P < 0.05 compared with the control group, ^#P < 0.05 compared with the model group.

Figure 3.

Comparisons of serum concentrations of IL-6, TNF-α, IL-1, and IL-10 among the three groups. At 24 hours after sepsis modeling, carotid blood was collected and centrifuged for separation of serum. (a) Comparisons of serum IL-6 concentrations among the three groups: compared with the control group, serum IL-6 concentrations in the model and observation groups were higher (P < 0.05); the concentration of IL-6 was higher in the observation group than in the control group (P < 0.05), but was significantly lower than that in the model group (P < 0.05). (b) Comparisons of serum TNF-α concentrations among the three groups: compared with the control group, serum TNF-α concentrations in the model and observation groups were higher (P < 0.05); the concentration of TNF-α was higher in the observation group than in the control group (P < 0.05), but was significantly lower than that in the model group (P < 0.05). (c) Comparisons of serum IL-1 concentrations among the three groups: compared with the control group, serum IL-1 concentrations in the model and observation groups were higher (P < 0.05); the concentration of IL-1 was higher in the observation group than in the control group (P < 0.05), but was significantly lower than that in the model group (P < 0.05). (d) Comparisons of serum IL-10 concentrations among the three groups: compared with the control group, serum IL-10 concentrations in the model and observation groups were higher (P < 0.05); the concentration of IL-10 was significantly higher in the observation group than in the control group (P < 0.05), but was significantly lower than that in the model group (P < 0.05). *P < 0.05; IL, interleukin; TNF, tumor necrosis factor.

Figure 4.

Comparisons of serum MDA concentrations and serum SOD activities among the three groups. At 24 hours after sepsis modeling, carotid blood was collected and centrifuged for separation of serum. (a) Comparisons of serum MDA concentrations among the three groups: the serum MDA concentration was significantly higher in the model group than in either observation or control groups (P < 0.05); serum MDA concentration was significantly higher in the observation group than in the control group (P < 0.05). (b) Comparisons of serum SOD activities among the three groups: the serum SOD activity was significantly lower in the model group than in either observation or control groups (P < 0.05); serum SOD activity was significantly lower in the observation group than in the control group (P < 0.05). *P < 0.05, MDA, malondialdehyde; SOD, superoxide dismutase.