Role of HMGB1 in apoptosis-mediated sepsis lethality |
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Authors: | Qin Shixin Wang Haichao Yuan Renqi Li Hui Ochani Mahendar Ochani Kanta Rosas-Ballina Mauricio Czura Chris J Huston Jared M Miller Ed Lin Xinchun Sherry Barbara Kumar Anjali Larosa Greg Newman Walter Tracey Kevin J Yang Huan |
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Affiliation: | Critical Therapeutics, Inc., Lexington, MA 02421, USA. |
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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. |
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