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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/R1538    most recent 00272.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Levy, R. M. Articles by Billiar, T. R. Search for Related Content PubMed PubMed Citation Articles by Levy, R. M. Articles by Billiar, T. R.

INFLAMMATION AND CYTOKINES

Systemic inflammation and remote organ injury following trauma require HMGB1

¹Departments of Surgery and ²Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; ³Laboratory of Biomedical Sciences, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York; and ⁴Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 20 April 2007 ; accepted in final form 25 July 2007

High-mobility group box 1 (HMGB1) is a 30-kDa DNA-binding protein that displays proinflammatory cytokine-like properties. HMGB1-dependent inflammatory processes have been demonstrated in models of sterile injury, including ischemia-reperfusion injury and hemorrhagic shock. Here, we tested the hypothesis that the systemic inflammatory response and associated remote organ injury that occur after peripheral tissue injury are highly dependent on HMGB1. Toll-like receptor 4 (TLR4) wild-type (WT) mice subjected to bilateral femur fracture after treatment with neutralizing antibodies to HMGB1 had lower serum IL-6 and IL-10 levels compared with mice treated with nonimmune control IgG. Similarly, compared with injured mice treated with control IgG, anti-HMGB1 antibody-treated mice had lower serum alanine aminotransferase levels and decreased hepatic and gut mucosal NF-B DNA binding. TLR4 mutant (C3H/HeJ) mice subjected to bilateral femur fracture had less systemic inflammation and liver injury than WT controls. Residual trauma-induced systemic inflammation and hepatocellular injury were not ameliorated by treatment with a polyclonal anti-HMGB1 antibody, even though HMGB1 levels were transiently elevated just 1 h after injury in both WT and C3H/HeJ mice. Collectively, these data demonstrate a critical role for a TLR4-HMGB1 pathway in the initiation of systemic inflammation and end-organ injury following isolated peripheral tissue injury.

femur fracture; damage-associated molecular pattern molecule; pattern recognition receptor, danger signal; tissue injury

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