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 non-severe 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 while the plasminogen activator inhibitor-1 (PAI-1) correlated positively with IL-6. Plg deficiency render mice susceptible to non-severe sepsis induced by cecal ligation and puncture (CLP), showing higher numbers of neutrophils and M1 macrophages, liver fibrin(ogen) deposition, lower efferocytosis and increased IL-6 and neutrophil extracellular traps (NETs) 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. Altogether, Plg/Pla are important host protective players during sepsis, controlling local and systemic inflammation and collateral organ damage.

Predicting valuable missense variants with AlphaMissense in a multiple pulmonary infection patient

“…This observation demonstrates a negative correlation between the severity of sepsis and PLG levels. 13 It confirms the protective effect of PLG against sepsis-induced lethality and enhances the protective effects of antibiotics.…”

“…This deficiency is characterized by increased numbers of neutrophils and macrophages, reduced efferocytosis, and elevated IL-6, which are associated with organ damage. 13 Herein, we report a comprehensive analysis that encompasses the application of genomics filtering to WES data, as well as the predictions of disease-associated genes using AlphaMissense and Phenolyzer to prioritize candidate genes based on phenotypic assessment. We employed Phenolyzer to analyze missense variants associated with the patient's phenotype.…”

Bionic Functional Surgical Suture with Hierarchical Micro–Nano Dimensions for Rotator Cuff Repair: Inducing Process‐Matching Mechanobiological and Biological Responses Adapted to the Regeneration

“…The thrombin-mediated release of fibrinopeptides from Fg converts this soluble protein into a three-dimensional network of Fb fibers, which is required for cellular chemotaxis and physiological hemostasis. [54,55] This three-dimensional network of Fb fibers is where blood clots are created. [54,55] The Fb network is also determined to have immunomodulatory effects, including lowering neutrophil extracellular traps and triggering macrophage reprogramming for M2 phenotypic polarization.…”

“…[54,55] This three-dimensional network of Fb fibers is where blood clots are created. [54,55] The Fb network is also determined to have immunomodulatory effects, including lowering neutrophil extracellular traps and triggering macrophage reprogramming for M2 phenotypic polarization. [55,56] We further noted that the FTIR spectra displayed the peptide bonds (-CO-NH; 1,641 cm À1 ) and -NH2 (3455 cm À1 ) groups in TC-nySS (Figure 1g), which indicated the successful chemical modification of the crosslinked fibrin networks on the fundamental micro-nano hierarchies structure.…”

“…[54,55] The Fb network is also determined to have immunomodulatory effects, including lowering neutrophil extracellular traps and triggering macrophage reprogramming for M2 phenotypic polarization. [55,56] We further noted that the FTIR spectra displayed the peptide bonds (-CO-NH; 1,641 cm À1 ) and -NH2 (3455 cm À1 ) groups in TC-nySS (Figure 1g), which indicated the successful chemical modification of the crosslinked fibrin networks on the fundamental micro-nano hierarchies structure. In this context, it was demonstrated that the three-dimensional network of Fb was successfully formed on the micro-nanosized nys as a TC modification of the TC-nySS biochemically.…”