Role of HMGB1 in apoptosis-mediated sepsis lethality.

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.

• Authors: Shixin Qin, Haichao Wang, Renqi Yuan, Hui Li, Mahendar Ochani, Kanta Ochani, Mauricio Rosas-Ballina, Chris J Czura, Jared M Huston, Ed Miller, Xinchun Lin, Barbara Sherry, Anjali Kumar, Greg Larosa, Walter Newman, Kevin J Tracey, Huan Yang
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 203 Issue 7 Pg. 1637-42 (Jul 10 2006) ISSN: 0022-1007 [Print] United States
• PMID: 16818669 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Antibodies, Monoclonal
• Caspase Inhibitors
• HMGB1 Protein
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Antibodies, Monoclonal (therapeutic use)
• Apoptosis (drug effects, immunology)
• Caspase Inhibitors
• Female
• HMGB1 Protein (immunology, physiology)
• Male
• Mice
• Mice, Inbred BALB C
• Sepsis (immunology, mortality, pathology, therapy)