Plasmin and plasminogen prevent sepsis severity by reducing neutrophil extracellular traps and systemic inflammation
Juliana P. Vago, Isabella Zaidan, Luiza O. Perucci, Larissa Froede Brito, Lívia C.R. Teixeira, Camila Meirelles Souza Silva, Thaís C. Miranda, Eliza M. Melo, Alexandre S. Bruno, Celso Martins Queiroz-Junior, Michelle A. Sugimoto, Luciana P. Tavares, Laís C. Grossi, Isabela N. Borges, Ayda Henriques Schneider, Nagyung Baik, Ayda H. Schneider, André Talvani, Raphael G. Ferreira, José C. Alves-Filho, Vandack Nobre, Mauro M. Teixeira, Robert J. Parmer, Lindsey A. Miles, Lirlândia P. Sousa
Juliana P. Vago, Isabella Zaidan, Luiza O. Perucci, Larissa Froede Brito, Lívia C.R. Teixeira, Camila Meirelles Souza Silva, Thaís C. Miranda, Eliza M. Melo, Alexandre S. Bruno, Celso Martins Queiroz-Junior, Michelle A. Sugimoto, Luciana P. Tavares, Laís C. Grossi, Isabela N. Borges, Ayda Henriques Schneider, Nagyung Baik, Ayda H. Schneider, André Talvani, Raphael G. Ferreira, José C. Alves-Filho, Vandack Nobre, Mauro M. Teixeira, Robert J. Parmer, Lindsey A. Miles, Lirlândia P. Sousa
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Research Article Infectious disease

Plasmin and plasminogen prevent sepsis severity by reducing neutrophil extracellular traps and systemic inflammation

Abstract

Sepsis is a lethal syndrome characterized by systemic inflammation and abnormal coagulation. Despite therapeutic advances, sepsis mortality remains substantially high. Herein, we investigated the role of the plasminogen/plasmin (Plg/Pla) system during sepsis. Plasma levels of Plg were significantly lower in mice subjected to severe compared with nonsevere sepsis, whereas systemic levels of IL-6, a marker of sepsis severity, were higher in severe sepsis. Plg levels correlated negatively with IL-6 in both septic mice and patients, whereas plasminogen activator inhibitor-1 levels correlated positively with IL-6. Plg deficiency render mice susceptible to nonsevere sepsis induced by cecal ligation and puncture (CLP), resulting in greater numbers of neutrophils and M1 macrophages, liver fibrin(ogen) deposition, lower efferocytosis, and increased IL-6 and neutrophil extracellular trap (NET) release associated with organ damage. Conversely, inflammatory features, fibrin(ogen), and organ damage were substantially reduced, and efferocytosis was increased by exogenous Pla given during CLP- and LPS-induced endotoxemia. Plg or Pla protected mice from sepsis-induced lethality and enhanced the protective effect of antibiotics. Mechanistically, Plg/Pla–afforded protection was associated with regulation of NET release, requiring Pla-protease activity and lysine binding sites. Plg/Pla are important host-protective players during sepsis, controlling local and systemic inflammation and collateral organ damage.

Authors

Juliana P. Vago, Isabella Zaidan, Luiza O. Perucci, Larissa Froede Brito, Lívia C.R. Teixeira, Camila Meirelles Souza Silva, Thaís C. Miranda, Eliza M. Melo, Alexandre S. Bruno, Celso Martins Queiroz-Junior, Michelle A. Sugimoto, Luciana P. Tavares, Laís C. Grossi, Isabela N. Borges, Ayda Henriques Schneider, Nagyung Baik, Ayda H. Schneider, André Talvani, Raphael G. Ferreira, José C. Alves-Filho, Vandack Nobre, Mauro M. Teixeira, Robert J. Parmer, Lindsey A. Miles, Lirlândia P. Sousa

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Figure 1

Evaluation of the survival rates and levels of Plg and IL-6 in plasma of mice after severe and nonsevere sepsis.

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Evaluation of the survival rates and levels of Plg and IL-6 in plasma of...
C57BL/6J mice were subjected to severe (18G needle) and nonsevere (30G needle) CLP. (A) The survival rates (n = 6 mice) were monitored for 6 days. (B and C) The levels of Plg (B) and IL-6 (C) were measured in plasma by ELISA 12 hours after CLP. (D) The correlation between plasma Plg and IL-6 levels was evaluated by Pearson’s coefficients. Results are shown as the mean ± SEM of at least 5 mice per group. The experiments were performed 3 times with similar results. ***P < 0.001 when comparing sham with severe CLP groups. #P < 0.05 or ###P < 0.001 when comparing severe and nonsevere sepsis groups (1-way ANOVA with post hoc Newman-Keuls).