Mechanism of Action
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 like H3 and H4 mediate endothelial cell death and sepsis.
Histones are proteins present in the nucleus, forming 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, the nucleosome. Generally, histones are restricted to the nucleus where these 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 septic cascade starts with a microbiological stimulus leading to the death of host cells. Histones are toxic to endothelial cells, their death results in further release of histones. Damage of endothelial cells leads to massive coagulation consuming coagulation factors and organ failure.
