Role of HMGB1 in apoptosis-mediated sepsis lethality.
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.
Qin
Shixin
S
Critical Therapeutics, Inc., Lexington, MA 02421, USA.
Wang
Haichao
H
Yuan
Renqi
R
Li
Hui
H
Ochani
Mahendar
M
Ochani
Kanta
K
Rosas-Ballina
Mauricio
M
Czura
Chris J
CJ
Huston
Jared M
JM
Miller
Ed
E
Lin
Xinchun
X
Sherry
Barbara
B
Kumar
Anjali
A
Larosa
Greg
G
Newman
Walter
W
Tracey
Kevin J
KJ
Yang
Huan
H
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D061945:Caspase Inhibitors; D005260:Female; D024243:HMGB1 Protein / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018805:Sepsis / Q000276:immunology / Q000401:mortality* / Q000473:pathology* / Q000628:therapy
D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D061945:Caspase Inhibitors; D024243:HMGB1 Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone