Circulating Histones Are Major Mediators of Multiple Organ Dysfunction Syndrome in Acute Critical Illnesses 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. Dr. Cheng performed animal experiments and sample analysis. Dr. Cheng, Dr. Abrams, and Mr. Toh performed the cell viability assay. Dr. Abrams analyzed the clinical data and performed statistical analysis as well as figure and article editing. Dr. Alhamdi collected part of the clinical data. Drs. Yu, Wang, and Toh supervised the work and wrote, edited, and reviewed the article and figures. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). This work was supported by the Medical Research Council (G0501641), British Heart Foundation (PG/14/19/30751 and PG/16/65/32313), and National Institute of Health Research (II-FS-0110-14061)and received scholarships from China Scholarship Council (CSC:20160609156) and Southeast University (YBJJ1740) to Dr. Cheng. Dr. Cheng, Dr. Abrams, Mr. Toh, Dr. Yu, Dr. Wang, and Dr. Toh’s institutions received funding from Medical Research Council (G0501641), British Heart Foundation (PG/14/19/30751 and PG/16/65/32313), and National Institute of Health Research (II-FS-0110-14061). Drs. Cheng, Abrams, Yu, Wang, and Toh received support for article research from Research Councils UK (RCUK). Drs. Cheng, Yu, and Wang disclosed government work. Dr. Alhamdi has disclosed that he does not have any potential conflicts of interest. For information regarding this article, correspondence via E-mail to: wpylg@hotmail.com; wangg@liverpool.ac.uk; toh@liverpool.ac.uk Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.