SHORT COMMUNICATION Nuclear histones: major virulence factors or just additional early sepsis markers? A comment Isaac Ginsburg 1 • Erez Koren 1,2,4 • James Varani 3 • Ron Kohen 2 Received: 20 June 2016 / Accepted: 29 August 2016 / Published online: 9 September 2016 Ó Springer International Publishing 2016 Abstract In 2009, Xu et al. and Chaput et al. in Nature Medicine had argued that the main cause of death in sepsis is the release from neutrophil nets of nuclear histone, highly toxic to endothelial cells and that these polycations are major and unique virulence factors. Since 2009, numerous researchers have also suggested the involvement of histones in the pathophysiology of many clinical disor- ders. If histones are indeed major unique virulence toxic agents, then heparin, activated protein C and antibodies to histone should prove excellent antisepsis agents. However, this is provided that these agents are administered to patients early enough before the activation of the cytokine storms, immune responses and the coagulation cascades are irreversibly unleashed. This may not be practical, since a diagnosis of sepsis is usually made much later. Future identifications of novel early markers are therefore needed and a compilation of cocktails of antagonists may replace the faulty single antagonists tried for many years, but in vain, to prevent death in sepsis. Keywords Nuclear histone Á Sepsis Á Septic shock Á Post-infectious sequelae Á Synergistic mechanisms Circulating histones in sepsis and in post- traumatic events Two ‘‘breakthrough’’ articles in Nature Medicine from 2009 (Chaput and Zychlinsky 2009; Xu et al. 2009) had argued to be the first to suggest that the main cause of death in sepsis may be the release from neutrophil extracellular traps (NETosis) of highly cationic histones possessing high toxicity to endothelial cells. This commences immuno- logical (cytokines storms) and coagulation cascades culminating in septic shock and death. In their study, Xu et al. showed that activated protein C (APC), a protease, cleaved histones and reduced lethality. However, blockade of APC activation exacerbated sub-lethal LPS challenge into lethality, which was reversed by antibody to histone. Chaput et al. assessed the protective effects of recombinant thrombomodulin (rTM), which was approved in Japan for the treatment of disseminated intravascular coagulation (DIC) and is currently undergoing a phase III clinical trial in the USA. Both groups of investigators had concluded and advised that extracellular histones may be the potential molecular targets for therapeutics for sepsis and additional post-in- fectious inflammatory and traumatic manifestations. If substantiated, the possibility that histone neutralization by heparins, but especially by the newly reported non-anti- coagulant heparin (Wildhagen et al. 2014), may be a blessed future hope for critical care patients combating post-infectious and inflammatory sequelae. It may interest the readers that already during the years 1951–1965, Katchalski’s group at the Weizmann Institute of Science in Rehovot, Israel, had described for the first time that the histone mimics poly-L-lysine and poly-L- arginine, injured blood vessels of rats, retarded blood coagulation and inhibited fibrinolysis (Biezunski et al. & Isaac Ginsburg Ginsburg@mail.huji.ac.il 1 Faculty of Dental Medicine, Institute of Dental Sciences, Hebrew University of Jerusalem, Jerusalem, Israel 2 Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel 3 Department of Pathology, University of Michigan, Ann Arbor, MI, USA 4 Present Address: Teva Pharmaceuticals Ltd, Kfar Saba, Israel Inflammopharmacol (2016) 24:287–289 DOI 10.1007/s10787-016-0279-y Inflammopharmacology 123