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. In fact, elevated levels of histones are present in human circulation in hyperinflammatory states such as acute respiratory distress syndrome 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 acute respiratory distress syndrome 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 acute respiratory distress syndrome and sepsis, and discuss the future potential of anti-histone therapy for treatment of these life-threatening disorders.

Keywords: acute respiratory distress syndrome (ARDS); coagulation; endothelial dysfunction; histones; lung injury; sepsis.

Fig. 1.

Mechanisms of histone release and its role in induction of ARDS. Injurious insults such as trauma and bacterial/viral pathogens induce the release of histones to the extracellular space as result of apoptosis, NETosis, or necrotic cell death. Histones released into circulation contribute to severity of ARDS/sepsis by various mechanisms, including direct endothelial cell death, coagulation, thrombosis, and production of inflammatory cytokines. Histone-blocking antibodies and other histone-neutralizing molecules, such as APC and heparin that bind or degrade histones, inhibit their cytotoxic effects and promote tissue recovery. EC: endothelial cell; PMN: polymorphonuclear leukocytes; NET: neutrophil extracellular traps; APC: activated protein C; ARDS: acute respiratory distress syndrome.

Fig. 2.

Mechanisms of histone-induced toxicity leading to ARDS. Histones stimulate the release of inflammatory chemokines and cytokines via TLR-dependent pathways or by activating NLRP3 inflammasome. Additionally, histones cause endothelial barrier disruption via yet-to-be-investigated mechanisms leading to increased vascular permeability and exacerbation of inflammatory response. Histones also increase thrombin generation by acting through TLRs or by directly binding to prothrombin and platelets. Multiple intracellular signaling pathways involving stress-induced kinases and other signaling kinases mediate histone-induced platelet activation and subsequent thrombin production. ARDS: acute respiratory distress syndrome; TLR: toll-like receptor.