| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
2 Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
3 Surgery, North Shore University Hospital, Manhasset, New York, United States
4 Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
5 Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States; Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
6 Surgery, University of Pittsburgh, United States
* To whom correspondence should be addressed. E-mail: billiartr{at}upmc.edu.
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)-
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.
This article has been cited by other articles:
|
|
 |
|
  D. J. Kaczorowski, K. P. Mollen, R. Edmonds, and T. R. Billiar Early events in the recognition of danger signals after tissue injury J. Leukoc. Biol., March 1, 2008; 83(3): 546 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. P. Mollen, R. M. Levy, J. M. Prince, R. A. Hoffman, M. J. Scott, D. J. Kaczorowski, R. Vallabhaneni, Y. Vodovotz, and T. R. Billiar Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow-derived cells and parenchymal cells J. Leukoc. Biol., January 1, 2008; 83(1): 80 - 88. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
