| Title | Systemic Inflammation and Remote Organ Injury Following Trauma Require HMGB1. | | Author(s) | Levy RM, Mollen KP, Prince JM, Kaczorowski DJ, Vallabhaneni R, Liu S, Tracey KJ, Lotze MT, Hackam DJ, Fink MP, Vodovotz Y, Billiar TR | | Institution | Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States. | | Source | Am J Physiol Regul Integr Comp Physiol 2007 Jul 25. | | Abstract | High mobility group box 1 (HMGB1) is a 30 kD DNA-binding protein that displays pro-inflammatory 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 to mice treated with non-immune control IgG. Similarly, compared to injured mice treated with control IgG, anti-HMGB1 antibody-treated mice had lower serum alanine aminotransferase (ALT) levels and decreased hepatic and gut mucosal nuclear factor (NF)-kappaB 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. Key words: femur fracture, Damage associated molecular pattern (DAMP) molecule, Pattern recognition receptor (PRR), danger signal, tissue injury. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 17652366 |
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