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Cyclosporin A and a non-immunosuppressive derivative (NIM 811) improve survival and mitochondrial myocardial dysfunction in a murine model of severe sepsis by cecal ligation and puncture

Introduction

We have previously shown that apoptotic and myocardial mitochondrial respiratory abnormalities, occurring during severe sepsis in a murine model, can be prevented by overexpression of Bcl-2, a regulatory protein of mitochondrial function. So, we sought to evaluate, in this model, a pharmacological modulation by cyclosporin A (CsA), a mitochondrial permeability transition pore (MPTP) inhibitor, and by its non-immunosuppressive derivative N-methyl-4-isoleucin CsA (NIM 811).

Materials and methods

Using a model of severe sepsis cecal ligation and puncture (CLP) induced (21-gauge needle) in female mice aged from 6 to 10 weeks, we studied the effects on 48-hour survival, echocardiographic data, myocardial apoptosis (nuclear apoptosis and caspase-3 and caspase-9 activation), and myocardial mitochondrial respiration, of MPTP inhibitors: CsA and NIM 811. A dose–response study was carried out with CsA in the following groups: CLP mice (n = 15), CLP + CsA 2 mg/kg (n = 8), CLP + CsA 10 mg/kg (n = 20), and CLP + CsA 100 mg/kg (n = 5). CsA was administered postoperatively, during the 1 ml subcutaneous injection for vascular filling. NIM 811 (dose of 2 mg/kg) was administered identically.

Results

Compared with sham, CLP mice present a low 48-hour survival (32% vs 90%; P < 0.05), an increased shortening fraction at H24, and a greater myocardial apoptotic activity. Forty-eight-hour survival in septic mice is significantly improved with use of CsA or NIM 811 (100% vs 32%; P < 0.05). Low (2 mg/kg) or moderate (10 mg/kg) doses of CsA improve 48-hour survival. Shortening fraction increases early at H6 in the CLP + CsA group, and is normalized at H24. Myocardial nuclear apoptosis and caspase-3 and caspase-9 activation are prevented by CsA and NIM 811. We also observed, in the CLP group, an early increase of oxygen consumption, at the complex IV level of the mitochondrial respiratory chain. This was also prevented by MPTP inhibitors in the CLP + CsA and CLP + NIM 811 groups.

Conclusion

These results suggest that mitochondrial respiration disruption could be responsible for myocardial dysfunction occurring during severe sepsis. To our knowledge, this is the first study addressing effects of NIM 811 in a severely septic animal model. Thus, the mitochondrial permeability transition pore constitutes a major target, and NIM 811 should be considered a therapeutic agent of potential great interest.

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Larché, J., Lancel, S., Gérard, A. et al. Cyclosporin A and a non-immunosuppressive derivative (NIM 811) improve survival and mitochondrial myocardial dysfunction in a murine model of severe sepsis by cecal ligation and puncture. Crit Care 9, P187 (2005). https://doi.org/10.1186/cc3250

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Keywords

  • Severe Sepsis
  • Mitochondrial Permeability Transition Pore
  • Myocardial Dysfunction
  • Mitochondrial Permeability Transition Pore
  • Cecal Ligation