Circulating histones are novel and important mediators of septic cardiomyopathy, which can potentially be utilized for prognostic and therapeutic purposes.

Developing an anti-infective shape-memory hemostatic sponge able to guide in situ tissue regeneration for noncompressible hemorrhages in civilian and battlefield settings remains a challenge. Here we engineer hemostatic chitosan sponges with highly interconnective microchannels by combining 3D printed microfiber leaching, freeze-drying, and superficial active modification. We demonstrate that the microchannelled alkylated chitosan sponge (MACS) exhibits the capacity for water and blood absorption, as well as rapid shape recovery. We show that compared to clinically used gauze, gelatin sponge, CELOX™, and CELOX™-gauze, the MACS provides higher pro-coagulant and hemostatic capacities in lethally normal and heparinized rat and pig liver perforation wound models. We demonstrate its anti-infective activity against S. aureus and E. coli and its promotion of liver parenchymal cell infiltration, vascularization, and tissue integration in a rat liver defect model. Overall, the MACS demonstrates promising clinical translational potential in treating lethal noncompressible hemorrhage and facilitating wound healing.

Objectives: Multiple organ dysfunction syndrome is characterized by simultaneous multiple organ failure, which is the leading cause of death in acute critically ill patients. However, what mediates multiple organ dysfunction syndrome is not fully understood. The discovery of toxic effects by extracellular histones on different individual organs strongly suggests their involvement in multiple organ dysfunction syndrome. In this study, we investigate whether circulating histones are major mediators of multiple organ dysfunction syndrome in acute critical illnesses. Design: Combination of retrospective clinical studies and animal models with intervention. Setting: ICU in a tertiary hospital and research laboratories. Patients: Four hundred and twenty ICU patients, including sepsis (140), severe trauma (63), severe pancreatitis (89), and other admission diagnoses (128). Laboratory Investigation: Cells from major organs are treated with calf thymus histones or histone-containing sera. Animal models for sepsis, trauma, and acute pancreatitis are treated with antihistone reagents. Intervention: Antihistone reagents in in vitro, ex vivo, and animal models. Measurement and Main Results: Retrospective analysis of a prospectively recruited ICU cohort demonstrated a strong correlation between circulating histones and organ injury markers and Sequential Organ Failure Assessment scores. Ex vivo experiments showed that patient sera containing high histone levels were toxic to cultured cells from different origins, suggesting their universal toxicity to multiple organs. Animal models of sepsis, trauma, and pancreatitis further demonstrated a temporal correlation between histone levels and disease severity and multiple organ injury. Importantly, antihistone reagents, that is, antihistone single-chain variable fragment and nonanticoagulant heparin, could dramatically reduce multiple organ injury, particularly of the heart and lungs, and improve survival in mouse models. Conclusions: High levels of circulating histones are major mediators of multiple organ dysfunction syndrome. Our results indicate that monitoring upon ICU admission could inform on disease severity and developing antihistone therapy holds great potential of reducing multiple organ dysfunction syndrome and improving survival of critically ill patients.

Sepsis was first described by the ancient Greek physicians over 2000 years ago. The pathophysiology of the disease, however, is still not fully understood and hence the mortality rate is still unacceptably high due to lack of specific therapies. In the last decade, great progress has been made by shifting the focus of research from systemic inflammatory response syndrome (SIRS) to multiple organ dysfunction syndrome (MODS). Sepsis has been re-defined as infection-induced MODS in 2016. How infection leads to MODS is not clear, but what mediates MODS becomes the major topic in understanding the molecular mechanisms and developing specific therapies. Recently, the mechanism of infection-induced extensive immune cell death which releases a large quantity of damage-associated molecular patterns (DAMPs) and their roles in the development of MODS as well as immunosuppression during sepsis have attracted much attention. Growing evidence supports the hypothesis that DAMPs, including high-mobility group box 1 protein (HMGB1), cell-free DNA (cfDNA) and histones as well as neutrophil extracellular traps (NETs), may directly or indirectly contribute significantly to the development of MODS. Here, we provide an overview of the mechanisms and consequences of infection-induced extensive immune cell death during the development of sepsis. We also propose a pivotal pathway from a local infection to eventual sepsis and a potential combined therapeutic strategy for targeting sepsis.