Extracellular histones are clinically relevant mediators in the pathogenesis of acute respiratory distress syndrome

Abstract

BackgroundExtracellular histones were recently identified as an inflammatory mediator involved in the pathogenesis of various organ injuries. This study aimed to examine extracellular histone levels and their clinical implications in acute respiratory distress syndrome (ARDS) patients and to explore histone-mediated effects through ex-vivo investigations.MethodsExtracellular histones, cytokine profiles and clinical data from 96 ARDS patients and 30 healthy volunteers were obtained. Human bronchial epithelial cells (BEAS-2B), human pulmonary artery endothelial cells (HPAEC), and human monocytic U937 cells were exposed to bronchoalveolar lavage fluid (BALF) collected from ARDS patients, and cellular damage and cytokine production were assessed. Furthermore, the effect of histone-targeted interventions by heparin or anti-histone antibody was evaluated.ResultsPlasma and BALF extracellular histone levels were much higher in ARDS patients than in healthy controls. There was a significant association between extracellular histones and ARDS severity and mortality. In addition, extracellular histones correlated with an evident systemic inflammation detected in ARDS patients. Ex-vivo analysis further showed that ARDS patient’s BALF remarkably induced epithelial and endothelial cell damage and stimulated cytokine production in the supernatant of U937 cells. The adverse effects on these cells could be abrogated by heparin or anti-histone antibody.ConclusionsExtracellular histones in ARDS patients are excessively increased and may contribute to disease aggravation by inducing cellular damage and promoting systemic inflammation. Targeting extracellular histones may provide a promising approach for treating ARDS.Electronic supplementary materialThe online version of this article (10.1186/s12931-017-0651-5) contains supplementary material, which is available to authorized users.

Impact of Elevated Circulating Histones on Systemic Inflammation after Radiofrequency Ablation in Lung Cancer Patients

“…Accumulating evidence shows that circulating histones can lead to systemic inflammatory and toxic responses in a single or combined manner. For example, elevated circulating histones are directly cytotoxic to endothelial and epithelial cells, as well as several other cell types, possibly through disrupting cellular membrane and inducing increased transmembrane conductance, calcium influx, cell swelling, and cytolysis [ 25 , 26 ]. Moreover, circulating histones can regulate coagulation and thrombosis by promoting platelet aggregation and impairing the protein C-thrombomodulin system [ 12 ].…”

“…Moreover, circulating histones can regulate coagulation and thrombosis by promoting platelet aggregation and impairing the protein C-thrombomodulin system [ 12 ]. Most importantly, circulating histones can function as damage-associated molecular pattern (DAMP) molecules to trigger inflammatory response [ 19 , 26 ]. All of these mechanisms suggest a toxic and inflammatory role for circulating histones in multiple pathophysiological processes.…”

Targeting potential drivers of COVID-19: Neutrophil extracellular traps

“…Furthermore, neutrophils from patients with pneumonia-associated ARDS appear “primed” to form NETs, and both the extent of priming and the level of NETs in blood correlate with disease severity and mortality (Adrover et al, 2020; Bendib et al, 2019; Ebrahimi et al, 2018; Lefrançais et al, 2018; Mikacenic et al, 2018). Extracellular histones, likely partly originating from NETs, are elevated in the bronchoalveolar lavage fluid and plasma of ARDS patients (Lv et al, 2017). Naked histones are toxic to cells, and there is strong experimental evidence supporting a role for histones in ARDS and sepsis (Wygrecka et al, 2017; Xu et al, 2015).…”

Extracellular histones are clinically associated with primary graft dysfunction in human liver transplantation

“…9,10,25,28 Extracellular histones are discovered to have the ability to cause endothelial cytotoxicity, platelet activation and aggregation, and act as danger/damage-associated molecular patterns (DAMPs) to initiate and propagate the inammatory response, which may eventually lead to life threatening organ and tissue damages. [29][30][31] The pathological role for extracellular histones in various disease processes has been investigated. However, little is known about clinical relevance of extracellular histones with PGD in human liver transplantation.…”