Circulating Histones and Nucleosomes as Biomarkers in Sepsis and Septic Shock

Mateo, Carlos Roma; Cervera, Marta Seco; Cabellos, José Santiago Ibañez; Pallardó, Federico V.

doi:10.1016/b978-0-12-801899-6.00025-5

Cited by 4 publications

(3 citation statements)

References 102 publications

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“…Histones have been detected in plasma of human patients with sepsis and septic shock reaching levels higher than 70 µg/mL [6,17,42]. Since several therapeutic strategies have failed in treating sepsis and septic shock [43], we consider relevant to characterize the mechanisms mediated by extracellular histones [20,44].…”

Section: Discussionmentioning

confidence: 99%

Extracellular histones activate autophagy and apoptosis via mTOR signaling in human endothelial cells

Ibáñez-Cabellos

Aguado

Pérez‐Cremades

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Circulating histones have been proposed as targets for therapy in sepsis and hyperinflammatory symptoms. However, the proposed strategies have failed in clinical trials. Although different mechanisms for histone-related cytotoxicity are being explored, those mediated by circulating histones are not fully understood. Extracellular histones induce endothelial cell death, thereby contributing to the pathogenesis of complex diseases such as sepsis and septic shock. Therefore, the comprehension of cellular responses triggered by histones is capital to design effective therapeutic strategies. Here we report how extracellular histones induce autophagy and apoptosis in a dose-dependent manner in cultured human endothelial cells. In addition, we describe how histones regulate these pathways via Sestrin2/AMPK/ULK1-mTOR and AKT/mTOR. Furthermore, we evaluate the effect of Toll-like receptors in mediating autophagy and apoptosis demonstrating how TLR inhibitors do not prevent apoptosis and/or autophagy induced by histones. Our results confirm that histones and autophagic pathways can be considered as novel targets to design therapeutic strategies in endothelial damage.

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Section: Discussionmentioning

confidence: 99%

Extracellular histones activate autophagy and apoptosis via mTOR signaling in human endothelial cells

Ibáñez-Cabellos

Aguado

Pérez‐Cremades

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…In summary, histone proteins, either in form of NETs, nucleosomes, or as individual proteins, are responsible for endothelial cell damage by means of several transduction pathways which are not fully understood [12][13][14][15][16]. The cell death consequences of the presence of histones in blood suggest that they could be used as disease progression biomarkers [17,18]. In this regard, there is also evidence for the participation of another nuclear protein, High-Mobility Group Box-1 (HMGB1), as part of the cytokine storm triggered during the inflammatory response to infection [19].…”

Section: Introductionmentioning

confidence: 99%

“…Correlations between blood levels of nucleoproteins and disease severity [ 17 , 22 , 23 ] set the basis for detecting their circulating levels in the blood as a parameter that could predict the onset of sepsis in patients. Several detection methods to measure circulating histones, nucleosomes, and nucleoproteins have been developed in order to use these parameters as effective, time-saving biomarkers that could avoid the striking consequences of permanent histone levels in the blood or that could, at least, differentiate between those patients that should receive more aggressive treatments or earlier fluid resuscitation in order to avoid a fatal outcome.…”

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of Chromatin-Delivered Biomarkers in the Monitoring of Sepsis and Septic Shock: A Pilot Study

Beltrán-García

Manclús

García-López

et al. 2021

IJMS

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Sepsis management remains one of the most important challenges in modern clinical practice. Rapid progression from sepsis to septic shock is practically unpredictable, hence the critical need for sepsis biomarkers that can help clinicians in the management of patients to reduce the probability of a fatal outcome. Circulating nucleoproteins released during the inflammatory response to infection, including neutrophil extracellular traps, nucleosomes, and histones, and nuclear proteins like HMGB1, have been proposed as markers of disease progression since they are related to inflammation, oxidative stress, endothelial damage, and impairment of the coagulation response, among other pathological features. The aim of this work was to evaluate the actual potential for decision making/outcome prediction of the most commonly proposed chromatin-related biomarkers (i.e., nucleosomes, citrullinated H3, and HMGB1). To do this, we compared different ELISA measuring methods for quantifying plasma nucleoproteins in a cohort of critically ill patients diagnosed with sepsis or septic shock compared to nonseptic patients admitted to the intensive care unit (ICU), as well as to healthy subjects. Our results show that all studied biomarkers can be used to monitor sepsis progression, although they vary in their effectiveness to separate sepsis and septic shock patients. Our data suggest that HMGB1/citrullinated H3 determination in plasma is potentially the most promising clinical tool for the monitoring and stratification of septic patients.

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Extracellular histones trigger oxidative stress-dependent induction of the NF-kB/CAM pathway via TLR4 in endothelial cells

et al. 2022

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Extracellular histones have been reported to aggravate different pathophysiological processes by increasing vascular permeability, coagulopathy, and inflammation. In the present study, we elucidate how extracellular histones (10–100 µg/mL) concentration dependently increase cytosolic reactive oxygen species (ROS) production using human umbilical vein endothelial cells (HUVECs). Furthermore, we identify cyclooxygenase (COX) and NADPH oxidase (NOX) activity as sources of ROS production in extracellular histone-treated HUVEC. This COX/NOX-mediated ROS production is also involved in enhanced NF-kB activity and cell adhesion molecules (VCAM1 and ICAM1) expression in histone-treated HUVEC. Finally, by using different toll-like receptor (TLR) antagonists, we demonstrate the role of TLR4 in CAMs overexpression triggered by extracellular histones in endothelial cells. In conclusion, our data suggest that through TLR4 signaling, extracellular histones increase endothelial cell activation, a mechanism involving increased COX- and NOX-mediated ROS. These findings increase our understanding on how extracellular histones enhance systemic inflammatory responses in diseases in which histone release occurs as part of the pathological processes.

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Circulating Histones and Nucleosomes as Biomarkers in Sepsis and Septic Shock

Cited by 4 publications

References 102 publications

Extracellular histones activate autophagy and apoptosis via mTOR signaling in human endothelial cells

Extracellular histones activate autophagy and apoptosis via mTOR signaling in human endothelial cells

Comparative Analysis of Chromatin-Delivered Biomarkers in the Monitoring of Sepsis and Septic Shock: A Pilot Study

Extracellular histones trigger oxidative stress-dependent induction of the NF-kB/CAM pathway via TLR4 in endothelial cells

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