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1 Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
2 Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States; Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: billiartr{at}upmc.edu.
Extensive soft tissue injury and bone fracture are significant contributors to the initial systemic inflammatory response in multiply injured patients. Systemic inflammation can lead to organ dysfunction remote from the site of traumatic injury. The mechanisms underlying the recognition of peripheral injury and the subsequent activation of the immune response are unknown. Toll-like receptors (TLRs) recognize microbial products but also may recognize danger signals released from damaged tissues. Here we report that peripheral tissue trauma initiates systemic inflammation and remote organ dysfunction. Moreover, this systemic response to a sterile local injury requires toll-like receptor 4 (TLR4). Compared to wild-type (C3H/HeOuJ) mice, TLR4 mutant (C3H/HeJ) mice demonstrated reduced systemic and hepatic inflammatory responses to bilateral femur fracture. Trauma-induced nuclear factor (NF)-
B activation in the liver required functional TLR4 signaling. CD14-/- mice failed to demonstrate protection from fracture-induced systemic inflammation and hepatocellular injury. Therefore, our results also argue against a contribution of intestine-derived lipopolysaccharide (LPS) to this process. These findings identify a critical role for TLR4 in the rapid recognition and response pathway to severe traumatic injury. Application of these findings in an evolutionary context suggests
that multi-cellular organisms have evolved to utilize the same pattern recognition receptor for surviving traumatic and infectious challenges.
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