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Is Histone a Solitary Vile Sepsis-Inducing Agent or Just "a Member of the Gang"?

Isaac Ginsburg, Erez Koren, Uriel Trahtemberg and Peter Vernon van Heerden

In this communication we argue that it is improbable that the main cause of death in sepsis is that, upon release of extracellular traps from neutrophils adhering to endothelial cells, highly cationic toxic histones uniquely cause endothelial dysregulation, organ failure and death. Activation of neutrophils is always accompanied by a plethora of pro-inflammatory agents, which may act in synergy with histones to injure cells. Furthermore, many recent articles have shown a steep rise of circulating histones in many clinical disorders unrelated to sepsis. We argue therefore that histones do not act as unique alarmins with an outsized role, but are probably another marker of cell damage.