Skip to main content
Erschienen in: Clinical Orthopaedics and Related Research® 9/2013

01.09.2013 | Symposium: Tscherne Festschrift

Cumulative Effects of Bone and Soft Tissue Injury on Systemic Inflammation: A Pilot Study

verfasst von: Roman Pfeifer, MD, Sophie Darwiche, MD, Lauryn Kohut, MA, Timothy R. Billiar, MD, FACS, Hans-Christoph Pape, MD, FACS

Erschienen in: Clinical Orthopaedics and Related Research® | Ausgabe 9/2013

Einloggen, um Zugang zu erhalten

Abstract

Background

In multiply injured patients, bilateral femur fractures invoke a substantial systemic inflammatory impact and remote organ dysfunction. However, it is unclear whether isolated bone or soft tissue injury contributes to the systemic inflammatory response and organ injury after fracture.

Questions/purposes

We therefore asked whether the systemic inflammatory response and remote organ dysfunction are attributable to the bone fragment injection, adjacent soft tissue injury, or both.

Methods

Male C57/BL6 mice (8–10 weeks old, 20–30 g) were assigned to four groups: bone fragment injection (BF, n = 9) group; soft tissue injury (STI, n = 9) group; BF + STI (n = 9) group, in which both insults were applied; and control group, in which neither insult was applied. Animals were sacrificed at 6 hours. As surrogates for systemic inflammation, we measured serum IL-6, IL-10, osteopontin, and alanine aminotransferase (ALT) and nuclear factor (NF)-κB and myeloperoxidase (MPO) in the lung.

Results

The systemic inflammatory response (mean IL-6 level) was similar in the BF (61.8 pg/mL) and STI (67.9 pg/mL) groups. The combination (BF + STI) of both traumatic insults induced an increase in mean levels of inflammatory parameters (IL-6: 189.1 pg/mL) but not in MPO levels (1.21 ng/mL) as compared with the BF (0.82 ng/mL) and STI (1.26 ng/mL) groups. The model produced little evidence of remote organ inflammation.

Conclusions

Our findings suggest both bone and soft tissue injury are required to induce systemic changes. The absence of remote organ inflammation suggests further fracture-associated factors, such as hemorrhage and fat liberation, may be more critical for induction of remote organ damage.

Clinical Relevance

Both bone and soft tissue injuries contribute to the systemic inflammatory response.
Literatur
1.
Zurück zum Zitat Akkose S, Ozgurer A, Bulut M, Koksal O, Ozdemir F, Ozguc H. Relationships between markers of inflammation, severity of injury, and clinical outcomes in hemorrhagic shock. Adv Ther. 2007;24:955–962.PubMedCrossRef Akkose S, Ozgurer A, Bulut M, Koksal O, Ozdemir F, Ozguc H. Relationships between markers of inflammation, severity of injury, and clinical outcomes in hemorrhagic shock. Adv Ther. 2007;24:955–962.PubMedCrossRef
2.
Zurück zum Zitat Ayala A, Wang P, Ba ZF, Perrin MM, Ertel W, Chaudry IH. Differential alterations in plasma IL-6 and TNF levels after trauma and hemorrhage. Am J Physiol. 1991;260(1 pt 2):R167–R171.PubMed Ayala A, Wang P, Ba ZF, Perrin MM, Ertel W, Chaudry IH. Differential alterations in plasma IL-6 and TNF levels after trauma and hemorrhage. Am J Physiol. 1991;260(1 pt 2):R167–R171.PubMed
3.
Zurück zum Zitat Bardenheuer M, Obertacke U, Waydhas C, Nast-Kolb D; AG Polytrauma der DGU. [Epidemiology of severe multiple trauma: a prospective registration of preclinical and clinical supply] [in German]. Unfallchirurg. 2000;103:355–363.PubMedCrossRef Bardenheuer M, Obertacke U, Waydhas C, Nast-Kolb D; AG Polytrauma der DGU. [Epidemiology of severe multiple trauma: a prospective registration of preclinical and clinical supply] [in German]. Unfallchirurg. 2000;103:355–363.PubMedCrossRef
4.
Zurück zum Zitat Chen J, Raj N, Kim P, Andrejko KM, Deutschman CS. Intrahepatic nuclear factor-kB activity and a1-acid glycoprotein transcription do not predict outcome after cecal ligation and puncture in the rat. Crit Care Med. 2001;29:589–596.PubMedCrossRef Chen J, Raj N, Kim P, Andrejko KM, Deutschman CS. Intrahepatic nuclear factor-kB activity and a1-acid glycoprotein transcription do not predict outcome after cecal ligation and puncture in the rat. Crit Care Med. 2001;29:589–596.PubMedCrossRef
5.
Zurück zum Zitat Chow CC, Clermont G, Kumar R, Lagoa C, Tawadrous Z, Gallo D, Betten B, Bartels J, Constantine G, Fink MP, Billiar TR, Vodovotz Y. The acute inflammatory response in diverse shock states. Shock. 2005;24:74–84.PubMedCrossRef Chow CC, Clermont G, Kumar R, Lagoa C, Tawadrous Z, Gallo D, Betten B, Bartels J, Constantine G, Fink MP, Billiar TR, Vodovotz Y. The acute inflammatory response in diverse shock states. Shock. 2005;24:74–84.PubMedCrossRef
6.
Zurück zum Zitat Copeland CE, Mitchell KA, Brumback RJ, Gens DR, Burgess AR. Mortality in patients with bilateral femoral fractures. J Orthop Trauma. 1998;12:315–319.PubMedCrossRef Copeland CE, Mitchell KA, Brumback RJ, Gens DR, Burgess AR. Mortality in patients with bilateral femoral fractures. J Orthop Trauma. 1998;12:315–319.PubMedCrossRef
7.
Zurück zum Zitat Darwiche SS, Pfeifer R, Menzel CL, Ruan X, Hoffman M, Cai C, Chanthaphavong RS, Loughran P, Pitt BR, Hoffman R, Pape HC, Billiar TR. Inducible nitric oxide synthase contributes to immune dysfunction following trauma. Shock. 2012;38:499–507.PubMedCrossRef Darwiche SS, Pfeifer R, Menzel CL, Ruan X, Hoffman M, Cai C, Chanthaphavong RS, Loughran P, Pitt BR, Hoffman R, Pape HC, Billiar TR. Inducible nitric oxide synthase contributes to immune dysfunction following trauma. Shock. 2012;38:499–507.PubMedCrossRef
8.
Zurück zum Zitat Denhardt DT, Guo X. Osteopontin: a protein with diverse functions. FASEB J. 1993;7:1475–1482.PubMed Denhardt DT, Guo X. Osteopontin: a protein with diverse functions. FASEB J. 1993;7:1475–1482.PubMed
9.
Zurück zum Zitat Flohe SB, Bangen JM, Flohe S, Agrawal H, Bergmann K, Schade FU. Origin of immunomodulation after soft tissue trauma: potential involvement of extracellular heat-shock proteins. Shock. 2007;27:494–502.PubMedCrossRef Flohe SB, Bangen JM, Flohe S, Agrawal H, Bergmann K, Schade FU. Origin of immunomodulation after soft tissue trauma: potential involvement of extracellular heat-shock proteins. Shock. 2007;27:494–502.PubMedCrossRef
10.
Zurück zum Zitat Gebhard F, Pfetsch H, Steinbach G, Stecker W, Kinzl L, Brückner UB. Is interleukin 6 an early marker of injury severity following major trauma in humans. Arch Surg. 2000;135:291–295.PubMedCrossRef Gebhard F, Pfetsch H, Steinbach G, Stecker W, Kinzl L, Brückner UB. Is interleukin 6 an early marker of injury severity following major trauma in humans. Arch Surg. 2000;135:291–295.PubMedCrossRef
11.
Zurück zum Zitat Giannoudis PV, Harwood PJ, Loughenbury P, van Griensven M, Krettek C, Pape HC. Correlation between IL-6 levels and the systemic inflammatory response score: can an IL-6 cutoff predict a SIRS state? J Trauma. 2008;65:646–652.PubMedCrossRef Giannoudis PV, Harwood PJ, Loughenbury P, van Griensven M, Krettek C, Pape HC. Correlation between IL-6 levels and the systemic inflammatory response score: can an IL-6 cutoff predict a SIRS state? J Trauma. 2008;65:646–652.PubMedCrossRef
12.
Zurück zum Zitat Gross S, Gammon ST, Moss B, Rauch D, Harding J, Heinecke JW, Ratner L, Piwnica-Worms D. Bioluminescence imaging of myeloperoxidase activity in vivo. Nat Med. 2009;15:455–461.PubMedCrossRef Gross S, Gammon ST, Moss B, Rauch D, Harding J, Heinecke JW, Ratner L, Piwnica-Worms D. Bioluminescence imaging of myeloperoxidase activity in vivo. Nat Med. 2009;15:455–461.PubMedCrossRef
13.
Zurück zum Zitat Harwood PJ, Giannoudis PV, van Griensven M, Krettek C, Pape HC. Alterations in the systemic inflammatory response after early total care and damage control procedures for femoral shaft fractures in severely injured patients. J Trauma. 2005;58:446–454.PubMedCrossRef Harwood PJ, Giannoudis PV, van Griensven M, Krettek C, Pape HC. Alterations in the systemic inflammatory response after early total care and damage control procedures for femoral shaft fractures in severely injured patients. J Trauma. 2005;58:446–454.PubMedCrossRef
14.
Zurück zum Zitat Hauser C, Zhou X, Joshi P, Cuchens MA, Kregor P, Devidas M, Kennedy RJ, Poole GV, Hughes JL. The immune microenvironment of human fracture/soft-tissue hematomas and its relationship to systemic immunity. J Trauma. 1997;42:895–904.PubMedCrossRef Hauser C, Zhou X, Joshi P, Cuchens MA, Kregor P, Devidas M, Kennedy RJ, Poole GV, Hughes JL. The immune microenvironment of human fracture/soft-tissue hematomas and its relationship to systemic immunity. J Trauma. 1997;42:895–904.PubMedCrossRef
15.
Zurück zum Zitat Hildebrand F, Pape HC, Krettek C. The importance of cytokines in the posttraumatic inflammatory reaction. Unfallchirurg. 2005;108:793–803.PubMedCrossRef Hildebrand F, Pape HC, Krettek C. The importance of cytokines in the posttraumatic inflammatory reaction. Unfallchirurg. 2005;108:793–803.PubMedCrossRef
16.
Zurück zum Zitat Johnson KD, Cadambi A, Seibert GB. Incidence of adult respiratory distress syndrome in patients with multiple musculoskeletal injuries: effect of early operative stabilisation of fractures. J Trauma. 1985;25:375–384.PubMedCrossRef Johnson KD, Cadambi A, Seibert GB. Incidence of adult respiratory distress syndrome in patients with multiple musculoskeletal injuries: effect of early operative stabilisation of fractures. J Trauma. 1985;25:375–384.PubMedCrossRef
17.
Zurück zum Zitat Kobbe P, Kaczorowski DJ, Vodovotz Y, Tzioupis CH, Mollen KP, Billiar TR, Pape HC. Local exposure of bone components to injured soft tissue induces Toll-like-receptor-4 dependent systemic inflammation with acute lung injury. Shock. 2008;30:686–691.PubMedCrossRef Kobbe P, Kaczorowski DJ, Vodovotz Y, Tzioupis CH, Mollen KP, Billiar TR, Pape HC. Local exposure of bone components to injured soft tissue induces Toll-like-receptor-4 dependent systemic inflammation with acute lung injury. Shock. 2008;30:686–691.PubMedCrossRef
18.
Zurück zum Zitat Kobbe P, Vodovotz Y, Kaczorowski D, Mollen KP, Billiar TR, Pape HC. Patterns of cytokine release and evolution of remote organ dysfunction after bilateral femur fracture. Shock. 2008;30:43–47.PubMedCrossRef Kobbe P, Vodovotz Y, Kaczorowski D, Mollen KP, Billiar TR, Pape HC. Patterns of cytokine release and evolution of remote organ dysfunction after bilateral femur fracture. Shock. 2008;30:43–47.PubMedCrossRef
19.
Zurück zum Zitat Kobbe P, Vodovotz Y, Kaczorowski DJ, Billiar TR, Pape HC. 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;22:385–390.PubMedCrossRef Kobbe P, Vodovotz Y, Kaczorowski DJ, Billiar TR, Pape HC. 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;22:385–390.PubMedCrossRef
20.
Zurück zum Zitat Koh A, Batista da Silva AP, Bansal AK, Bansal M, Sun C, Lee H, Glogauer M, Sodek J, Zohar R. Role of osteopontin in neutrophil function. Immunology. 2007;122:466–475.PubMedCrossRef Koh A, Batista da Silva AP, Bansal AK, Bansal M, Sun C, Lee H, Glogauer M, Sodek J, Zohar R. Role of osteopontin in neutrophil function. Immunology. 2007;122:466–475.PubMedCrossRef
21.
Zurück zum Zitat Levy RM, Prince JM, Yang R, Mollen KP, Liao H, Watson GA, Fink MP, Vodovotz Y, Billiar TR. 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–R976.PubMedCrossRef Levy RM, Prince JM, Yang R, Mollen KP, Liao H, Watson GA, Fink MP, Vodovotz Y, Billiar TR. 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–R976.PubMedCrossRef
22.
Zurück zum Zitat Menzel CL, Pfeifer R, Darwiche SS, Kobbe P, Gill R, Shapiro RA, Loughran P, Vodovotz Y, Scott MJ, Zenati MS, Billiar TR, Pape HC. Models of lower extremity damage in mice: time course of organ damage and immune response. J Surg Res. 2011;166:e149–e156.PubMedCrossRef Menzel CL, Pfeifer R, Darwiche SS, Kobbe P, Gill R, Shapiro RA, Loughran P, Vodovotz Y, Scott MJ, Zenati MS, Billiar TR, Pape HC. Models of lower extremity damage in mice: time course of organ damage and immune response. J Surg Res. 2011;166:e149–e156.PubMedCrossRef
23.
Zurück zum Zitat Mori R, Shaw TJ, Martin P. Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J Exp Med. 2008;205:43–51.PubMedCrossRef Mori R, Shaw TJ, Martin P. Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J Exp Med. 2008;205:43–51.PubMedCrossRef
24.
Zurück zum Zitat Neidhardt R, Keel M, Steckholzer, U Safret A, Ungethuem U, Trentz O, Ertel W. Relationship of interleukin-10 plasma levels to severity of injury and clinical outcome in injured patients. J Trauma. 1997;42:863–871.PubMedCrossRef Neidhardt R, Keel M, Steckholzer, U Safret A, Ungethuem U, Trentz O, Ertel W. Relationship of interleukin-10 plasma levels to severity of injury and clinical outcome in injured patients. J Trauma. 1997;42:863–871.PubMedCrossRef
25.
Zurück zum Zitat Pape HC, Schmidt R, Rice J van Griensven M, das Gupta R, Krettek C, Tscherne H. Biochemical changes after trauma and skeletal surgery of the lower extremity: quantification of the operative burden. Crit Care Med. 2000;28:3441–3448.PubMedCrossRef Pape HC, Schmidt R, Rice J van Griensven M, das Gupta R, Krettek C, Tscherne H. Biochemical changes after trauma and skeletal surgery of the lower extremity: quantification of the operative burden. Crit Care Med. 2000;28:3441–3448.PubMedCrossRef
26.
Zurück zum Zitat Perl M, Gebhard F, Knöferl MW, Bachem M, Gross HJ, Kinzl L, Strecker W. The pattern of preformed cytokines in tissues frequently affected by trauma. Shock. 2003;19:299–304.PubMedCrossRef Perl M, Gebhard F, Knöferl MW, Bachem M, Gross HJ, Kinzl L, Strecker W. The pattern of preformed cytokines in tissues frequently affected by trauma. Shock. 2003;19:299–304.PubMedCrossRef
27.
Zurück zum Zitat Pfeifer R, Kobbe P, Darwiche S, Billiar TR, Pape HC. Role of hemorrhage in the induction of systemic inflammation and remote organ damage: analysis of combined pseudo-fracture and hemorrhagic shock. J Orthop Res. 2011;29:270–274.PubMedCrossRef Pfeifer R, Kobbe P, Darwiche S, Billiar TR, Pape HC. Role of hemorrhage in the induction of systemic inflammation and remote organ damage: analysis of combined pseudo-fracture and hemorrhagic shock. J Orthop Res. 2011;29:270–274.PubMedCrossRef
28.
Zurück zum Zitat Robinson CM. Current concepts of respiratory insufficiency syndromes after fracture. J Bone Joint Surg Br. 2001;83:781–791.PubMedCrossRef Robinson CM. Current concepts of respiratory insufficiency syndromes after fracture. J Bone Joint Surg Br. 2001;83:781–791.PubMedCrossRef
29.
Zurück zum Zitat Rose S, Marzi I. Mediators in polytrauma—pathophysiological significance and clinical relevance. Langenbeck’s Arch Surg. 1998;383:199–208.CrossRef Rose S, Marzi I. Mediators in polytrauma—pathophysiological significance and clinical relevance. Langenbeck’s Arch Surg. 1998;383:199–208.CrossRef
30.
Zurück zum Zitat Roumen RM, Hendriks T, van der Ven-Jongekrijg J, Nieuwenhuijzen GA, Sauerwein RW, van der Meer JW, Goris RJ. Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Ann Surg. 1993;218:769–776.PubMedCrossRef Roumen RM, Hendriks T, van der Ven-Jongekrijg J, Nieuwenhuijzen GA, Sauerwein RW, van der Meer JW, Goris RJ. Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Ann Surg. 1993;218:769–776.PubMedCrossRef
31.
Zurück zum Zitat Schemitsch EH, Turchin DC, Anderson GI, Byrick RJ, Mullen JB, Richards RR. Pulmonary and systemic fat embolization after medullary canal pressurization: a hemodynamic and histologic investigation in the dog. J Trauma. 1998;45:738–742.PubMedCrossRef Schemitsch EH, Turchin DC, Anderson GI, Byrick RJ, Mullen JB, Richards RR. Pulmonary and systemic fat embolization after medullary canal pressurization: a hemodynamic and histologic investigation in the dog. J Trauma. 1998;45:738–742.PubMedCrossRef
32.
Zurück zum Zitat Schmidt-Bleek K, Schell H, Kolar P, Pfaff M, Perka C, Buttgereit F, Duda G, Lienau J. Cellular composition of the initial fracture hematoma compared to a muscle hematoma: a study in sheep. J Orthop Res. 2009;27:1147–1151.PubMedCrossRef Schmidt-Bleek K, Schell H, Kolar P, Pfaff M, Perka C, Buttgereit F, Duda G, Lienau J. Cellular composition of the initial fracture hematoma compared to a muscle hematoma: a study in sheep. J Orthop Res. 2009;27:1147–1151.PubMedCrossRef
33.
Zurück zum Zitat Schmitz D, Bangen J, Herborn C, Husain B, Lendemans S, Flohé SB, Metz KA, Schade FU, Taeger G, Oberbeck JR, Kobbe P, Waydhas C, Flohé S. Isolated closed minor-muscle injury of lower leg did not cause an obvious systemic immune response. Inflamm Res. 2010;59:141–149.PubMedCrossRef Schmitz D, Bangen J, Herborn C, Husain B, Lendemans S, Flohé SB, Metz KA, Schade FU, Taeger G, Oberbeck JR, Kobbe P, Waydhas C, Flohé S. Isolated closed minor-muscle injury of lower leg did not cause an obvious systemic immune response. Inflamm Res. 2010;59:141–149.PubMedCrossRef
34.
35.
Zurück zum Zitat Willett K, Al-Khateeb H, Kotnis R, Bouamra O, Lecky F. Risk of mortality: the relationship with associated injuries and fracture treatment methods in patients with unilateral or bilateral femoral shaft fractures. J Trauma. 2010;69:405–410.PubMedCrossRef Willett K, Al-Khateeb H, Kotnis R, Bouamra O, Lecky F. Risk of mortality: the relationship with associated injuries and fracture treatment methods in patients with unilateral or bilateral femoral shaft fractures. J Trauma. 2010;69:405–410.PubMedCrossRef
Metadaten
Titel
Cumulative Effects of Bone and Soft Tissue Injury on Systemic Inflammation: A Pilot Study
verfasst von
Roman Pfeifer, MD
Sophie Darwiche, MD
Lauryn Kohut, MA
Timothy R. Billiar, MD, FACS
Hans-Christoph Pape, MD, FACS
Publikationsdatum
01.09.2013
Verlag
Springer US
Erschienen in
Clinical Orthopaedics and Related Research® / Ausgabe 9/2013
Print ISSN: 0009-921X
Elektronische ISSN: 1528-1132
DOI
https://doi.org/10.1007/s11999-013-2908-8

Weitere Artikel der Ausgabe 9/2013

Clinical Orthopaedics and Related Research® 9/2013 Zur Ausgabe

Notice of Redundant Publication

Notice of Redundant Publication

Arthropedia

Grundlagenwissen der Arthroskopie und Gelenkchirurgie. Erweitert durch Fallbeispiele, Videos und Abbildungen. 
» Jetzt entdecken

Update Orthopädie und Unfallchirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.