Targeting circulating high mobility group box-1 and histones by extracorporeal blood purification as an immunomodulation strategy against critical illnesses

Both high mobility group box-1 (HMGB1) and histones are major damage-associated molecular patterns (DAPMs) that mediate lethal systemic inflammation, activation of the complement and coagulation system, endothelial injury and multiple organ dysfunction syndrome in critical illnesses. Although accumulating evidence collectively shows that targeting HMGB1 or histones by their specific antibodies or inhibitors could significantly mitigate aberrant immune responses in multiple critically ill animal models, routine clinical use of such agents is still not recommended by any guideline. In contrast, extracorporeal blood purification, which has been widely used to replace dysfunctional organs and remove exogenous or endogenous toxins in intensive care units, may also exert an immunomodulatory effect by eliminating inflammatory mediators such as cytokines, endotoxin, HMGB1 and histones in patients with critical illnesses. In this review, we summarize the multiple immunopathological roles of HMGB1 and histones in mediating inflammation, immune thrombosis and organ dysfunction and discuss the rationale for the removal of these DAMPs using various hemofilters. The latest preclinical and clinical evidence for the use of extracorporeal blood purification to improve the clinical outcome of critically ill patients by targeting circulating HMGB1 and histones is also gathered.

Automated summary

Both HMGB1 and histones play major roles in mediating inflammation, immune thrombosis, and organ dysfunction in critical illnesses. Targeting them with specific antibodies or inhibitors has shown promise in animal models, but their routine clinical use is not recommended. On the other hand, extracorporeal blood purification may remove these DAMPs and exert an immunomodulatory effect in critically ill patients. This review summarizes the immunopathological roles of HMGB1 and histones, discusses the rationale for using hemofilters to remove these DAMPs, and gathers the latest evidence for the use of extracorporeal blood purification to improve clinical outcomes in critically ill patients.