Role of HMGB1 in apoptosis-mediated sepsis lethality

Author:

Qin Shixin1,Wang Haichao2,Yuan Renqi3,Li Hui3,Ochani Mahendar3,Ochani Kanta3,Rosas-Ballina Mauricio3,Czura Chris J.3,Huston Jared M.3,Miller Ed4,Lin Xinchun4,Sherry Barbara5,Kumar Anjali1,LaRosa Greg1,Newman Walter1,Tracey Kevin J.35,Yang Huan35

Affiliation:

1. Critical Therapeutics, Inc., Lexington, MA 02421

2. Department of Emergency Medicine

3. Laboratory of Biomedical Science,

4. Department of Surgery, North Shore University Hospital

5. Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY 11030

Abstract

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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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