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Septic diaphragmatic dysfunction is prevented by Mn(III)porphyrin therapy and inducible nitric oxide synthase inhibition

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Abstract

Objective

Decreased diaphragmatic contractility and organ failure observed during sepsis is mediated by an overproduction of nitric oxide (.NO)-derived species, mitochondria being a major target of oxidative and nitrative stress. We tested the potential protective effects of (a) a novel synthetic antioxidant, the manganese(III) 5,10,15,20-tetrakis(N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP5+) and (b) the inducible .NO synthase inhibitor aminoguanidine (AG) on a rat model of sepsis.

Setting

University research laboratories.

Subjects and interventions

Sepsis was induced by cecal ligation and perforation in rats.

Measurements and results

Systemic hemodynamics, pulmonary gas exchange, in vitro diaphragmatic function and mitochondrial respiration were evaluated. Moreover, plasma and mitochondrial oxidative and nitrative stress parameters were investigated. Sepsis determined diaphragmatic dysfunction and a significant decrease in mitochondrial coupling and respiration. Oxidative stress was evidenced by decreased plasma antioxidants and increased lipid oxidation. Tyrosine nitration was increased in the plasma and mitochondria of the septic animals. These alterations were ameliorated or prevented by either MnTE-2-PyP5+ or AG.

Conclusions

Our results demonstrate that overproduction of .NO and .NO-derived reactive species play a critical role in mitochondrial impairment and diaphragmatic function during sepsis. More importantly, AG but mainly the novel metalloporphyrin MnTE-2-PyP5+ were able to ameliorate diaphragmatic and mitochondrial dysfunction and could contribute to preventing organ failure during severe sepsis.

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Acknowledgements

We thank Ines Batinic-Haberle from Duke University for providing the MnTE-2-PyP5+.

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Authors and Affiliations

  1. Department of Pathophysiology, Hospital de Clínicas, School of Medicine, Universidad de la República , Avenida Italia s/n, Piso 15, CP 11600, Montevideo, Uruguay

    Nicolás Nin, José Boggia, Evangelina Alfonso & F. Javier Hurtado

  2. Department of Biochemistry and Center for Free Radical and Biomedical Research, School of Medicine, Universidad de la República, Avenida General Flores 2125, CP 11800, Montevideo, Uruguay

    Adriana Cassina, Horacio Botti, Gonzalo Peluffo, Andrés Trostchansky, Carlos Batthyány, Rafael Radi & Homero Rubbo

Authors
  1. Nicolás Nin
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  2. Adriana Cassina
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  4. Evangelina Alfonso
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  9. Rafael Radi
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  10. Homero Rubbo
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  11. F. Javier Hurtado
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Corresponding author

Correspondence to F. Javier Hurtado.

Additional information

This work was supported in part by FOGARTY-NIH, Wellcome Trust and Guggenheim Foundation for Homero Rubbo and Rafael Radi, and the Howard Hughes Medical Institute for Rafael Radi, and by PRONBIO, Fundación Manuel Pérez for Nicolás Nin.

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Nin, N., Cassina, A., Boggia, J. et al. Septic diaphragmatic dysfunction is prevented by Mn(III)porphyrin therapy and inducible nitric oxide synthase inhibition. Intensive Care Med 30, 2271–2278 (2004). https://doi.org/10.1007/s00134-004-2427-x

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  • DOI: https://doi.org/10.1007/s00134-004-2427-x

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