title: Splenectomy protects against sepsis lethality and reduces serum HMGB1 levels.
abstract: High mobility group box 1 (HMGB1) is a critical mediator of lethal sepsis. Previously, we showed that apoptotic cells can activate macrophages to release HMGB1. During sepsis, apoptosis occurs primarily in lymphoid organs, including the spleen and thymus. Currently, it is unclear whether this accelerated lymphoid organ apoptosis contributes to systemic release of HMGB1 in sepsis. In this study, we report that splenectomy significantly reduces systemic HMGB1 release and improves survival in mice with polymicrobial sepsis. Treatment with a broad-spectrum caspase inhibitor reduces systemic lymphocyte apoptosis, suppresses circulating HMGB1 concentrations, and improves survival during polymicrobial sepsis, but fails to protect septic mice following splenectomy. These findings indicate that apoptosis in the spleen is essential to the pathogenesis of HMGB1-mediated sepsis lethality.
authors: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
authors: Jared M
authors: JM
authors: Huston
authors: Haichao
authors: H
authors: Wang
authors: Mahendar
authors: M
authors: Ochani
authors: Kanta
authors: K
authors: Ochani
authors: Mauricio
authors: M
authors: Rosas-Ballina
authors: Margot
authors: M
authors: Gallowitsch-Puerta
authors: Mala
authors: M
authors: Ashok
authors: Lihong
authors: L
authors: Yang
authors: Kevin J
authors: KJ
authors: Tracey
authors: Huan
authors: H
authors: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D024243:HMGB1 Protein / Q000097:blood*; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D018805:Sepsis / Q000401:mortality / Q000628:therapy*; D013154:Spleen / Q000166:cytology; D013156:Splenectomy; D015996:Survival Rate
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D024243:HMGB1 Protein