Plasmin and plasminogen prevent sepsis severity by reducing neutrophil extracellular traps and systemic inflammation
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
|---|---|
| Enthalten in: |
JCI insight - 8(2023), 8 vom: 24. Apr. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Vago, Juliana P [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 25.04.2023 Date Revised 09.01.2024 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1172/jci.insight.166044 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM354227696 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM354227696 | ||
| 003 | DE-627 | ||
| 005 | 20240114232913.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1172/jci.insight.166044 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1253.xml |
| 035 | |a (DE-627)NLM354227696 | ||
| 035 | |a (NLM)36917195 | ||
| 035 | |a (PII)e166044 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Vago, Juliana P |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Plasmin and plasminogen prevent sepsis severity by reducing neutrophil extracellular traps and systemic inflammation |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 25.04.2023 | ||
| 500 | |a Date Revised 09.01.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Bacterial infections | |
| 650 | 4 | |a Infectious disease | |
| 650 | 4 | |a Plasmin | |
| 650 | 7 | |a Fibrinolysin |2 NLM | |
| 650 | 7 | |a EC 3.4.21.7 |2 NLM | |
| 650 | 7 | |a Plasminogen |2 NLM | |
| 650 | 7 | |a 9001-91-6 |2 NLM | |
| 650 | 7 | |a Interleukin-6 |2 NLM | |
| 650 | 7 | |a Fibrin |2 NLM | |
| 650 | 7 | |a 9001-31-4 |2 NLM | |
| 700 | 1 | |a Zaidan, Isabella |e verfasserin |4 aut | |
| 700 | 1 | |a Perucci, Luiza O |e verfasserin |4 aut | |
| 700 | 1 | |a Brito, Larissa Froede |e verfasserin |4 aut | |
| 700 | 1 | |a Teixeira, Lívia Cr |e verfasserin |4 aut | |
| 700 | 1 | |a Silva, Camila Meirelles Souza |e verfasserin |4 aut | |
| 700 | 1 | |a Miranda, Thaís C |e verfasserin |4 aut | |
| 700 | 1 | |a Melo, Eliza M |e verfasserin |4 aut | |
| 700 | 1 | |a Bruno, Alexandre S |e verfasserin |4 aut | |
| 700 | 1 | |a Queiroz-Junior, Celso Martins |e verfasserin |4 aut | |
| 700 | 1 | |a Sugimoto, Michelle A |e verfasserin |4 aut | |
| 700 | 1 | |a Tavares, Luciana P |e verfasserin |4 aut | |
| 700 | 1 | |a Grossi, Laís C |e verfasserin |4 aut | |
| 700 | 1 | |a Borges, Isabela N |e verfasserin |4 aut | |
| 700 | 1 | |a Schneider, Ayda Henriques |e verfasserin |4 aut | |
| 700 | 1 | |a Baik, Nagyung |e verfasserin |4 aut | |
| 700 | 1 | |a Schneider, Ayda H |e verfasserin |4 aut | |
| 700 | 1 | |a Talvani, André |e verfasserin |4 aut | |
| 700 | 1 | |a Ferreira, Raphael G |e verfasserin |4 aut | |
| 700 | 1 | |a Alves-Filho, José C |e verfasserin |4 aut | |
| 700 | 1 | |a Nobre, Vandack |e verfasserin |4 aut | |
| 700 | 1 | |a Teixeira, Mauro M |e verfasserin |4 aut | |
| 700 | 1 | |a Parmer, Robert J |e verfasserin |4 aut | |
| 700 | 1 | |a Miles, Lindsey A |e verfasserin |4 aut | |
| 700 | 1 | |a Sousa, Lirlândia P |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t JCI insight |d 2016 |g 8(2023), 8 vom: 24. Apr. |w (DE-627)NLM257703918 |x 2379-3708 |7 nnns |
| 773 | 1 | 8 | |g volume:8 |g year:2023 |g number:8 |g day:24 |g month:04 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1172/jci.insight.166044 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 8 |j 2023 |e 8 |b 24 |c 04 | ||