Abstract
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection and is associated with high morbidity and mortality. Circulating histones (CHs), a group of damage-associated molecular pattern molecules mainly derived from neutrophil extracellular traps, play a crucial role in sepsis by mediating inflammation response, organ injury and death through Toll-like receptors or inflammasome pathways. Herein, we first elucidate the molecular mechanisms of histone-induced inflammation amplification, endothelium injury and cascade coagulation activation, and discuss the close correlation between elevated level of CHs and disease severity as well as mortality in patients with sepsis. Furthermore, current state-of-the-art on anti-histone therapy with antibodies, histone-binding proteins (namely recombinant thrombomodulin and activated protein C), and heparin is summarized to propose promising approaches for sepsis treatment.
Highlights
Sepsis is a dysregulated host response secondary to infection, which leads to life-threatening multiple organ dysfunction syndrome (MODS) and subsequent death [1]
Once being released from necrotic cells, Circulating histones (CHs) exhibit toxic effects on pathogens and on host cells. They initiate and amplify dysregulated inflammatory response by activating Toll-like receptors (TLR) and the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, and induce endothelium injury as well as coagulation activation, which lead to MODS and death
Clinical studies have confirmed the close correlation between high levels of CHs and disease severity as well as mortality in sepsis, suggesting that CHs have the potential to predict the clinical outcome of sepsis
Summary
Sepsis is a dysregulated host response secondary to infection, which leads to life-threatening multiple organ dysfunction syndrome (MODS) and subsequent death [1]. Current clinical management of sepsis mainly includes broad-spectrum antibiotics therapy, fluid resuscitation, vasopressor administration, and organ support [4]. These conventional therapies overlook the immunopathological nature of sepsis and fail to further improve the survival rates of patients with severe sepsis and septic shock [5, 6]. Emphasis has recently been laid on identifying novel therapeutic targets and prognostic biomarkers for sepsis treatment to achieve proper and timely immunomodulation of this dysregulated immune response [7, 8]
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