Analysis of Inflammatory Mediator Profiles in Sepsis Patients Reveals That Extracellular Histones Are Strongly Elevated in Nonsurvivors

Abstract

The timely recognition of sepsis and the prediction of its clinical course are challenging due to the complex molecular mechanisms leading to organ failure and to the heterogeneity of sepsis patients. Treatment strategies relying on a “one-fits-all” approach have failed to reduce mortality, suggesting that therapeutic targets differ between patient subgroups and highlighting the need for accurate analysis of the molecular cascades to assess the highly variable host response. Here, we characterized a panel of 44 inflammatory mediators, including cytokines, chemokines, damage-associated molecular patterns, and coagulation-related factors, as well as markers of endothelial activation in 30 patients suffering from renal failure in the course of sepsis. All patients received continuous veno-venous hemodialysis with either high cut-off filters or with standard filters, and mediators were quantified for all patients at the initiation of dialysis and after 24 h and 48 h. Mediator concentrations in individual patients ranged widely, demonstrating the heterogeneity of sepsis patients. None of the mediators correlated with SAPS III or TISS scores. The overall in-hospital mortality of the study population was 56.7% (57.1% vs. 56.3% for high cut-off vs. standard filter). The two filter groups differed regarding most of the mediator levels at baseline, prohibiting conclusions regarding the effect of standard filters versus high cut-off filters on mediator depletion. The elevation and correlation of damage-associated molecular patterns and markers of endothelial activation gave evidence of severe tissue damage. In particular, extracellular histones were strongly increased and were almost 30-fold higher in nonsurvivors as compared to survivors, indicating their diagnostic and prognostic potential.

Activated Platelets and Platelet-Derived Extracellular Vesicles Mediate COVID-19-Associated Immunothrombosis

“…HMGB1 interacts with heparin via two positively charged domains, box A and box B ( Martinotti et al, 2015 ), and via its heparin-binding domain ( Xu et al, 2011 ). HMGB1 plasma levels are elevated in conditions associated with abnormal coagulation, including sepsis ( Eichhorn et al, 2021 ) and COVID-19, where HMGB1 has been correlated with disease severity ( Chen et al, 2020 ). The biological functions of HMGB1 resemble those of activated platelets, including the induction of DNA externalization in neutrophils ( Maugeri et al, 2014 ; Hoste et al, 2019 ) and microvascular thrombosis ( Ito et al, 2007 ).…”

A Fully Integrated Microfluidic Device with Immobilized Dyes for Simultaneous Detection of Cell-Free DNA and Histones from Plasma Using Dehydrated Agarose Gates

“…Notably, procalcitonin (PCT) and C-reactive protein (CRP) have been extensively considered biomarkers for the diagnosis and prognosis of sepsis [ 5 ]. More recently, cell-free DNA (cfDNA) and histones have been introduced as two biomarkers for sepsis prognosis which both reflects cellular death activity [ 2 , 6 , 7 , 8 , 9 , 10 ]. Nucleosomes consist of 145 bp DNA wrapped around a core histone octamer, which contains two copies of histones H2A, H2B, H3, and H4.…”

Neutrophil extracellular traps in urinary tract infection

“…Apart from antimicrobial defense of neutrophils (6,7), extracellular DNA (ecDNA) released during NETs formation is recognized as a damage-associated molecular pattern that further activates immune response. According to recent studies, markers of NETs formation can be perceived as markers of inflammation in a variety of pathologies including sepsis, multiple trauma, obesity, systemic autoimmune diseases and thrombosis (8)(9)(10)(11)(12)(13)(14)(15). Recently, studies of Yu and colleagues identified proteins derived from neutrophils (16) and NETs-like structures (17) in urine sediment of UTI patients.…”