title: Systemic inflammation and remote organ injury following trauma require HMGB1.
abstract: 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-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.
authors.affiliation: Dept. of Surgery, F-1200 PUH, Univ. of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15213, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Levy
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Mollen
authors.forename: Jose M
authors.initials: JM
authors.lastname: Prince
authors.forename: David J
authors.initials: DJ
authors.lastname: Kaczorowski
authors.forename: Raghuveer
authors.initials: R
authors.lastname: Vallabhaneni
authors.forename: Shiguang
authors.initials: S
authors.lastname: Liu
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: David J
authors.initials: DJ
authors.lastname: Hackam
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Fink
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
mesh_terms: D000818:Animals; D000906:Antibodies; D015415:Biomarkers; D050723:Fractures, Bone / Q000150:complications* / Q000378:metabolism; D024243:HMGB1 Protein / Q000235:genetics* / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014947:Wounds and Injuries
chemical_list: D000906:Antibodies; D015415:Biomarkers; D024243:HMGB1 Protein; D015850:Interleukin-6; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10