The Journal of Experimental Medicine
StemCell Technologies
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Published online 3 July 2006 doi:10.1084/jem.20052203
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 7, 1637-1642
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BRIEF DEFINITIVE REPORT

 Role of HMGB1 in apoptosis-mediated sepsis lethality

Shixin Qin1, Haichao Wang2, Renqi Yuan4, Hui Li4, Mahendar Ochani4, Kanta Ochani4, Mauricio Rosas-Ballina4, Chris J. Czura4, Jared M. Huston4, Ed Miller3, Xinchun Lin3, Barbara Sherry5, Anjali Kumar1, Greg LaRosa1, Walter Newman1, Kevin J. Tracey4,5, and Huan Yang4,5

1 Critical Therapeutics, Inc., Lexington, MA 02421
2 Department of Emergency Medicine, 3 Department of Surgery, North Shore University Hospital, 4 Laboratory of Biomedical Science, and 5 Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY 11030

CORRESPONDENCE Huan Yang: hyang{at}nshs.edu

Severe sepsis, a lethal syndrome after infection or injury, is the third leading cause of mortality in the United States. The pathogenesis of severe sepsis is characterized by organ damage and accumulation of apoptotic lymphocytes in the spleen, thymus, and other organs. To examine the potential causal relationships of apoptosis to organ damage, we administered Z-VAD-FMK, a broad-spectrum caspase inhibitor, to mice with sepsis. We found that Z-VAD-FMK–treated septic mice had decreased levels of high mobility group box 1 (HMGB1), a critical cytokine mediator of organ damage in severe sepsis, and suppressed apoptosis in the spleen and thymus. In vitro, apoptotic cells activate macrophages to release HMGB1. Monoclonal antibodies against HMGB1 conferred protection against organ damage but did not prevent the accumulation of apoptotic cells in the spleen. Thus, our data indicate that HMGB1 production is downstream of apoptosis on the final common pathway to organ damage in severe sepsis.


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