Haichao Wang, ^13* Ona Bloom, ³ Minghuang Zhang, ³ Jaideep M. Vishnubhakat, ³ Michael Ombrellino, ²³ Jiantu Che, ³ Asia Frazier, ²³ Huan Yang, ³ Svetlana Ivanova, ³ Lyudmila Borovikova, ³ Kirk R. Manogue, ³ Eugen Faist, ⁴ Edward Abraham, ⁵ Jan Andersson, ⁶ Ulf Andersson, ⁷ Patricia E. Molina, ² Naji N. Abumrad, ² Andrew Sama, ¹ Kevin J. Tracey ²³

Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

¹ Department of Emergency Medicine and
² Department of Surgery, North Shore University Hospital-New York University School of Medicine, Manhasset, NY 11030, USA.
³ The Picower Institute for Medical Research, Manhasset, NY 11030, USA.
⁴ Department of Surgery, Klinicum Grosshadern, Ludwig-Maximilians University, Munich, Germany.
⁵ Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
⁶ Department of Infectious Disease, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
⁷ Department of Rheumatology, Astrid Lindgren's Children's Hospital, Karolinska Institute, Stockholm, Sweden.
^*   To whom correspondence should be addressed. E-mail: hwang{at}picower.edu