The Role of Histones and Heparin in Sepsis: A Review

Abstract

Septic shock with multiple organ failure is a devastating situation in clinical settings. Through the past decades, much progress has been made in the management of sepsis and its underlying pathogenesis, but a highly effective therapeutic has not been developed. Recently, macromolecules such as histones have been targeted in the treatment of sepsis. Histones primarily function as chromosomal organizers to pack DNA and regulate its transcription through epigenetic mechanisms. However, a growing body of research has shown that histone family members can also exert cellular toxicity once they relocate from the nucleus into the extracellular space. Heparin, a commonly used anti-coagulant, has been shown to possess life-saving capabilities for septic patients, but the potential interplay between heparin and extracellular histones has not been investigated. In this review, we summarize the pathogenic roles of extracellular histones and the therapeutic roles of heparin in the development and management of sepsis and septic shock.

Circulating histones contribute to monocyte and MDW alterations as common mediators in classical and COVID-19 sepsis

“…The cut-offs reported for both MDW index and histone values are in agreement with literature references (healthy control subjects [ 5 , 6 , 11 , 12 , 15 ]; COVID-19 patients [ 12 , 14 , 15 ]; and Sepsis patients [ 5 , 6 , 11 ]).…”

“…We further compared these in vitro modifications to those measured in COVID-19 and Sepsis patients. The cut-offs reported for both MDW index and histone values are in agreement with literature references (healthy control subjects [5,6,11,12,15]; COVID-19 patients [12,14,15]; and Sepsis patients [5,6,11]).…”

“…For the first time, we demonstrated that histone concentrations similar to those found in critical COVID-19 condition [ 15 ], as well as in classical Sepsis [ 5 , 6 ], are able to induce significant morphological modifications and a time-dependent increase of MDW value, related to monocyte heterogeneity and inflammatory activation [ 17 ], characteristics of both SARS-CoV-2 infection [ 18 ] and critical Sepsis condition [ 2 , 11 ] (Fig. 1 D).…”

“…Moreover, recent observations suggest possible therapeutic approaches with polyanions (e.g., heparins, heparinoids) [ 10 ] as potential strategies for protecting tissues from histone-induced inflammation/thrombosis [ 5 , 19 ].…”

“…Histones are key components for chromatin physiological functions but extracellularly mobilized during pathological processes [1]. Acting as endogenous damage-associated molecular pattern molecules, histones mediate both inflammatory pathways and coagulative cascade linked to the severity of several pathologies, including Sepsis and COVID-19 [2][3][4][5][6]. In fact, histones interact with blood cells (e.g., monocytes and platelets) promoting cytotoxicity, inducing phosphatidylserine exposure, modulating Toll-like receptors, releasing pro-inflammatory cytokine/ chemokines and activating the coagulative cascade [1].…”