title: 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.affiliation: Critical Therapeutics, Inc., Lexington, MA 02421, USA.
authors.forename: Shixin
authors.initials: S
authors.lastname: Qin
authors.forename: Haichao
authors.initials: H
authors.lastname: Wang
authors.forename: Renqi
authors.initials: R
authors.lastname: Yuan
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Mahendar
authors.initials: M
authors.lastname: Ochani
authors.forename: Kanta
authors.initials: K
authors.lastname: Ochani
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rosas-Ballina
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Czura
authors.forename: Jared M
authors.initials: JM
authors.lastname: Huston
authors.forename: Ed
authors.initials: E
authors.lastname: Miller
authors.forename: Xinchun
authors.initials: X
authors.lastname: Lin
authors.forename: Barbara
authors.initials: B
authors.lastname: Sherry
authors.forename: Anjali
authors.initials: A
authors.lastname: Kumar
authors.forename: Greg
authors.initials: G
authors.lastname: Larosa
authors.forename: Walter
authors.initials: W
authors.lastname: Newman
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
mesh_terms: 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
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D061945:Caspase Inhibitors; D024243:HMGB1 Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone