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 2

Assessment of Plg levels and PAI-1 in serum of patients with sepsis and septic shock.

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Assessment of Plg levels and PAI-1 in serum of patients with sepsis and ...
Blood samples of patients with sepsis were centrifuged and serum levels of Plg, IL-6, and PAI-1 were measured by ELISA. (A and F) The association between these analytes was evaluated by correlation (Pearson’s coefficient, R) and regression analyses (R2). (B, C, G, and H) Plg and PAI-1 levels in patients with sepsis (n = 12) and septic shock (n = 10) were evaluated on day 1 (B and G) and day 3 (C and H) by unpaired 2-tailed Student’s t tests. (D and E) Sequential behavior of Plg levels on days 1 and 3 was evaluated in patients with sepsis (D) and patients with septic shock (E) by paired 2-tailed Student’s t test. *P < 0.05. Outliers were removed from the graphs when detected. Of note, Plg levels in patients with sepsis were measured in serum. Plg levels in both plasma and serum are similar, with serum displaying 16% less Plg than plasma, as previously described (75). Nonetheless, we found consistently high levels of Plg in serum samples from patients with sepsis in our study.