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Splenectomy Protects against Sepsis Lethality and Reduces Serum HMGB1 Levels¹

Jared M. Huston^*, Haichao Wang, Mahendar Ochani^*, Kanta Ochani^*, Mauricio Rosas-Ballina^*, Margot Gallowitsch-Puerta^*, Mala Ashok, Lihong Yang^*, Kevin J. Tracey^*, and Huan Yang^2,*,

^* Laboratory of Biomedical Science, Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York 11030; Department of Emergency Medicine, North Shore University Hospital, Manhasset, NY 11030

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Faculty Award Program and General Clinical Research Center of The Feinstein Institute for Medical Research (M01-RR018535) and the National Institute of General Medical Sciences (NIGMS) to K.J.T.

² Address correspondence and reprint requests to Dr. Huan Yang, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, New York 11030. E-mail address: hyang{at}nshs.edu

³ Abbreviations used in this paper: HMGB1, high mobility group box 1; Z-VAD-FMK, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone; Z-FA-FMK, benzyloxycarbonyl-Phe-Ala-fluoromethylketone; CLP, cecal ligation and puncture.

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The JI 2008 181: 2939-2940. [Full Text]  

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