Extracellular histones in lung dysfunction: a new biomarker and therapeutic target?

Abstract

Extracellular histones released from injured or dying cells following trauma and other severe insults can act as potent damage-associated molecular patterns (DAMPs). In fact, elevated levels of histones are present in human circulation in hyperinflammatory states such as acute respiratory distress syndrome (ARDS) and sepsis. The molecular mechanisms owing to histone-induced pathologies are at the very beginning of elucidating. However, neutralization of histones with antibodies, histone-binding or histone-degrading proteins and heparan sulfates have shown promising therapeutic effects in pre-clinical ARDS and sepsis models. Various cell types undergoing necrosis and apoptosis or activated neutrophils forming neutrophil extracellular traps have been implicated in excessive release of histones which further augments tissue injury and may culminate in multiple organ failure. At the molecular level, an uncontrolled inflammatory cascade has been considered as the major event; however, histone-activated coagulation and thrombosis represent additional pathologic events reflecting coagulopathy. Furthermore, epigenetic regulation and chemical modifications of circulating histones appear to be critically important in their biological functions as evidenced by increased cytotoxicity associated with citrullinated histone. Herein, we will briefly review the current knowledge on the role of histones in ARDS, sepsis and discuss the future potential of anti-histone therapy for treatment of these life-threatening disorders.

Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets

“…Conventional ELISA and Western blotting techniques to measure histone levels in patient samples so far need to be replaced with more sensitive and real-time monitoring assays such as detection by probes in situ . A careful analysis of histone subtypes as well as histone modifications (namely citrullinated histone) also needs to be done because of the significant variation in their toxicity ( 124 , 128 ). Another major area of investigation is on the discovery of novel anti-histone agents to eliminate the unexpected bleeding risk associated with the use of conventional heparin and thrombomodulin, etc.…”

Histones of Neutrophil Extracellular Traps (NETs) Activate Brain Pericyte via Dectin-1 in Traumatic Brain Injury

“…Circulating histones from necrotic or dead cells are highly associated with the severity and development of acute in ammatory diseases and ischemia-reperfusion injury [55,67]. In pre-clinical studies, neutralizing or degrading extracellular histones with speci c antibody or heparan sulfates have shown promising effects even though our understandings about histone-induced pathologies are still at the beginning [68]. We build the connection between NETs histones and CD11b induction in brain pericyte, illuminating the possible histone-related molecular mechanism in neuroin ammation.…”

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

“…DAMPs probably play a significant role in supporting cytokine storms, but comparatively little research has been expended in studying DAMPs as compared to PAMPs in this context, so the details of what roles DAMPs are playing in maintaining cytokine overproduction syndromes and how to intervene in their effects are vague [ 217 , 218 ]. Critically ill COVID-19 patients, ALI/ARDS patients and sepsis patients all release high levels of extracellular histones (TLR2, TLR4 and NLRP3 activators [ 219 ]); neutrophil elastase (a TLR4 activator [ 220 ]) and cell-free DNA (a TLR9 activator [ 221 ]), each of which correlate with the probability of the patients being admitted to the intensive care unit and of dying [ 222 ]. The nuclear protein high mobility group box 1 protein (HMGB1) is also released during severe COVID-19, ALI/ARDS and sepsis and drives TLR2 and TLR4 activation [ 223 ].…”