From the Guidelines
Elevated histones in the bloodstream are a marker of cell death or damage and should be managed by treating the underlying condition, with no specific medication directly targeting histones. The presence of elevated histones can indicate significant tissue injury, often seen in conditions like sepsis, trauma, or autoimmune disorders 1. Management of elevated histones focuses on treating the underlying condition causing cell death, such as using appropriate antibiotics and supportive care for sepsis, or immunosuppressants for autoimmune conditions. Some studies have explored the use of histone deacetylase inhibitors (HDIs) in certain conditions, which can affect histone modification and potentially influence disease progression 1. However, the use of HDIs is more relevant to specific diseases like cancer, where they can inhibit tumor proliferation by activating expression of tumor suppressor genes. In the context of managing elevated histones, monitoring their levels can help track disease progression and treatment response. Histones contribute to pathology by triggering inflammation and forming neutrophil extracellular traps (NETs) when released extracellularly, which can damage blood vessels and organs by activating platelets and promoting clotting 1. Therapeutic approaches that indirectly reduce histone levels include anti-inflammatory medications, anticoagulants, and treatments that stabilize cell membranes to prevent further cell death. It is essential to prioritize the treatment of the underlying condition causing elevated histones, rather than focusing solely on reducing histone levels. Key considerations in managing elevated histones include:
- Treating the underlying condition causing cell death
- Monitoring histone levels to track disease progression and treatment response
- Using therapeutic approaches that indirectly reduce histone levels, such as anti-inflammatory medications and anticoagulants
- Stabilizing cell membranes to prevent further cell death.
From the Research
Elevated Histones: Causes and Effects
- Elevated histones are present in human circulation in hyperinflammatory states such as acute respiratory distress syndrome and sepsis 2, 3
- The release of histones from injured or dying cells can act as potent damage-associated molecular patterns, leading to tissue injury and multiple organ failure 2, 4
- Various cell types undergoing necrosis and apoptosis or activated neutrophils forming neutrophil extracellular traps have been implicated in excessive release of histones 2, 4
Therapeutic Potential
- Neutralization of histones with antibodies, histone-binding or histone-degrading proteins, and heparan sulfates have shown promising therapeutic effects in pre-clinical acute respiratory distress syndrome and sepsis models 2, 3
- Anti-histone treatment has been shown to protect mice against lethal endotoxemia, sepsis, ischemia/reperfusion injury, trauma, pancreatitis, peritonitis, stroke, coagulation, and thrombosis 3
Biological Functions
- Histones have key roles in chromatin remodeling and gene transcription, and can act as microbicidal proteins and are pro-thrombotic 3, 4
- Extracellular histones can function as damage-associated molecular pattern molecules, activating Toll-like receptors and inflammasome pathways 3
- Epigenetic regulation and chemical modifications of circulating histones appear to be critically important in their biological functions 2
Regulation of Histone Levels
- Cells have evolved numerous strategies to limit the generation of excess histones and prevent deleterious effects due to their accumulation 5
- The synthesis of histone proteins is tightly regulated at multiple steps, and transcriptional as well as posttranscriptional regulation of histone proteins is well established 5, 6
- Excess histone levels can mediate cytotoxicity via multiple mechanisms, including saturation of histone modifying enzymes and non-specific binding to DNA and RNA 6