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Models of Lower Extremity Damage in Mice: Time Course of Organ Damage and Immune Response

Published:December 24, 2010DOI:https://doi.org/10.1016/j.jss.2010.11.914

      Background

      Post-traumatic inflammatory changes have been identified as major causes of altered organ function and failure. Both hemorrhage and soft tissue damage induce these inflammatory changes. Exposure to heterologous bone in animal models has recently been shown to mimic this inflammatory response in a stable and reproducible fashion. This follow-up study tests the hypothesis that inflammatory responses are comparable between a novel trauma model (“pseudofracture”, PFx) and a bilateral femur fracture (BFF) model.

      Materials and Methods

      In C57BL/6 mice, markers for remote organ dysfunction and inflammatory responses were compared in four groups (control/sham/BFF/PFx) at the time points 2, 4, and 6 h.

      Results

      Hepatocellular damage in BFF and PFx was highly comparable in extent and evolution, as shown by similar levels of NFkappaB activation and plasma ALT. Pulmonary inflammatory responses were also comparably elevated in both trauma models as early as 2 h after trauma as measured by myeloperoxidase activity (MPO). Muscle damage was provoked in both BFF and PFx mice over the time course, although BFF induced significantly higher AST and CK levels. IL-6 levels were also similar with early and sustained increases over time in both trauma models.

      Conclusions

      Both BFF and PFx create similar reproducible inflammatory and remote organ responses. PFx will be a useful model to study longer term inflammatory effects that cannot be studied using BFF.

      Key Words

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      References

        • Krug E.G.
        • Sharma G.K.
        • Lozano R.
        The global burden of injuries.
        Am J Public Health. 2000; 90: 523
        • Sauaia A.
        • Moore F.A.
        • Moore E.E.
        • et al.
        Epidemiology of trauma deaths: A reassessment.
        J Trauma. 1995; 38: 185
        • Demetriades D.
        • Murray J.
        • Charalambides K.
        • et al.
        Trauma fatalities: Time and location of hospital deaths.
        J Am Coll Surg. 2004; 198: 20
        • Meislin H.
        • Criss E.A.
        • Judkins D.
        • et al.
        Fatal trauma: The modal distribution of time to death is a function of patient demographics and regional resources.
        J Trauma. 1997; 43: 433
        • Flohé S.B.
        • Flohé S.
        • Schade F.U.
        Invited review: Deterioration of the immune system after trauma: Signals and cellular mechanisms.
        Innate Immun. 2008; 14: 333
        • Keel M.
        • Trentz O.
        Pathophysiology of polytrauma.
        Injury. 2005; 36: 691
        • Giannoudis P.V.
        Current concepts of the inflammatory response after major trauma: An update.
        Injury. 2003; 34: 397
        • Moore F.A.
        • Moore E.E.
        Evolving concepts in the pathogenesis of postinjury multiple organ failure.
        Surg Clin North Am. 1995; 75: 257
        • Levy R.M.
        • Mollen K.P.
        • Prince J.M.
        • et al.
        Systemic inflammation and remote organ injury following trauma require HMGB1.
        Am J Physiol Regul Integr Comp Physiol. 2007; 293: R1538
        • Levy R.M.
        • Prince J.M.
        • Yang R.
        • et al.
        Systemic inflammation and remote organ damage following bilateral femur fracture requires Toll-like receptor 4.
        Am J Physiol Regul Integr Comp Physiol. 2006; 291: R970
        • Mollen K.P.
        • Levy R.M.
        • Prince J.M.
        • et al.
        Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow-derived cells and parenchymal cells.
        J Leukoc Biol. 2008; 83: 80
        • Kobbe P.
        • Vodovotz Y.
        • Kaczorowski D.J.
        • Billiar T.R.
        • Pape H.C.
        The role of fracture-associated soft tissue injury in the induction of systemic inflammation and remote organ dysfunction after bilateral femur fracture.
        J Orthop Trauma. 2008; 22: 385
        • Tsukamoto T.
        • Pape H.C.
        Animal models for trauma research: What are the options?.
        Shock. 2008; 31: 3
        • Kobbe P.
        • Vodovotz Y.
        • Kaczorowski D.J.
        • et al.
        Patterns of cytokine release and evolution of remote organ dysfunction after bilateral femur fracture.
        Shock. 2008; 30: 43
        • Durham R.M.
        • Moran J.J.
        • Mazuski J.E.
        • et al.
        Multiple organ failure in trauma patients.
        J Trauma. 2003; 55: 608
        • Copeland C.E.
        • Mitchell K.A.
        • Brumback R.J.
        • et al.
        Mortality in patients with bilateral femoral fractures.
        J Orthop Trauma. 1998; 12: 315
        • Timlin M.
        • Condron C.
        • Toomey D.
        • et al.
        N-acetylcysteine attenuates lung injury in a rodent model of fracture.
        Acta Orthop Scand. 2004; 75: 61
        • Kobbe P.
        • Kaczorowski D.J.
        • Vodovotz Y.
        • et al.
        Local exposure of bone components to injured soft tissue induces toll-like-receptor-4 dependent systemic inflammation with acute lung injury.
        Shock. 2008; 30: 686
        • Kobbe P.
        • Stoffels B.
        • Schmidt J.
        • et al.
        IL-10 deficiency augments acute lung but not liver injury in hemorrhagic shock.
        Cytokine. 2009; 45: 26
        • Meert K.L.
        • Ofenstein J.P.
        • Sarnaik A.P.
        Altered T cell cytokine production following mechanical trauma.
        Ann Clin Lab Sci. 1998; 28: 283
        • Dewar D.
        • Moore F.A.
        • Moore E.E.
        • et al.
        Postinjury multiple organ failure.
        Injury. 2009; 40: 912
        • Brun-Buisson C.
        The epidemiology of the systemic inflammatory response.
        Intensive Care Med. 2000; 26: S64
        • Donnelly M.
        • Condron C.
        • Murray P.
        • et al.
        Modulation of the glycemic response using insulin attenuates the pulmonary response in an animal trauma model.
        J Trauma. 2007; 63: 351
        • Gray A.C.
        • White T.O.
        • Clutton E.
        • et al.
        The stress response to bilateral femoral fractures: A comparison of primary intramedullary nailing and external fixation.
        J Orthop Trauma. 2009; 23: 90
        • Efstathopoulos N.
        • Tsaganos T.
        • Giamarellos-Bourboulis E.J.
        • et al.
        Early apoptosis of monocytes contributes to the pathogenesis of systemic inflammatory response and of bacterial translocation in an experimental model of multiple trauma.
        Clin Exp Immunol. 2006; 145: 139
        • Werner U.
        • Szelenyi I.
        Measurement of MPO activity as model for detection of granulocyte infiltration in different tissues.
        Agents Actions. 1992; (Spec No:C101-C103)
        • Ayala A.
        • Chung C.S.
        • Lomas J.L.
        • et al.
        Shock-induced neutrophil mediated priming for acute lung injury in mice: Divergent effects of TLR-4 and TLR-4/FasL deficiency.
        Am J Path. 2002; 161: 2283
        • Biffl W.L.
        • Moore E.E.
        • Moore F.A.
        • et al.
        Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation?.
        Ann Surg. 1996; 224: 647
        • Sears B.W.
        • Stover M.D.
        • Callaci J.
        Pathoanatomy and clinical correlates of the immunoinflammatory response following orthopedic trauma.
        J Am Acad Orthop Surg. 2009; 14: 255
        • Shegarfi H.
        • Reikeras O.
        Review article: Bone transplantation and immune responses.
        J Orthop Surg (Hong Kong). 2009; 17: 206