Histones explained
Development of novel treatments for sepsis requires thorough understanding of the underlying pathophysiology. In sepsis, coagulation and inflammation processes interact closely with each other. Scientific evidence indicates that the extracellular histones H3 and H4 mediate endothelial cell death and sepsis.
Histones are basic proteins that are present in the nucleus where they form major components of eukaryotic chromatin and function to regulate transcription. The winding of genomic DNA around histone octamers forms the basic unit of packaged DNA termed the nucleosome. Generally, histones are restricted to the nucleus and are not considered toxic.
However, histones are also known to be part of the innate immune system and do kill microbes and human cells. A growing body of evidence indicates that histones can have cytoplasmic and extracellular localisations and actions. Histones and nucleosomes have been detected in the cytoplasm and have also been linked to apoptosis. It was demonstrated that extracellular histones are released in response to inflammatory challenges and are the main effectors of endothelial dysfunction, organ failure and death during sepsis.
A cascade starts by the septic stimulus leading to the death of human cells. Histones are toxic to endothelial cells, their death results in further release of histones. Damage of endothelial cells leads to massive coagulation consuming coagulant factors. Shortage of these molecules leads to bleeding in other parts of the body.
