Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Clinical Orthopaedics and Related Research®
Published 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

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

Published in: Clinical Orthopaedics and Related Research® | Issue 9/2013

Login to get access

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.
Literature
1.
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.
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.
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.
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.
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.
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.
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.
Denhardt DT, Guo X. Osteopontin: a protein with diverse functions. FASEB J. 1993;7:1475–1482.PubMed
9.
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.
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.
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.
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.
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.
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.
Hildebrand F, Pape HC, Krettek C. The importance of cytokines in the posttraumatic inflammatory reaction. Unfallchirurg. 2005;108:793–803.PubMedCrossRef
16.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Robinson CM. Current concepts of respiratory insufficiency syndromes after fracture. J Bone Joint Surg Br. 2001;83:781–791.PubMedCrossRef
29.
Rose S, Marzi I. Mediators in polytrauma—pathophysiological significance and clinical relevance. Langenbeck’s Arch Surg. 1998;383:199–208.CrossRef
30.
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.
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.
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.
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.
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
Metadata
Title
Cumulative Effects of Bone and Soft Tissue Injury on Systemic Inflammation: A Pilot Study
Authors
Roman Pfeifer, MD
Sophie Darwiche, MD
Lauryn Kohut, MA
Timothy R. Billiar, MD, FACS
Hans-Christoph Pape, MD, FACS
Publication date
01-09-2013
Publisher
Springer US
Published in
Clinical Orthopaedics and Related Research® / Issue 9/2013
Print ISSN: 0009-921X
Electronic ISSN: 1528-1132
DOI
https://doi.org/10.1007/s11999-013-2908-8

Other articles of this Issue 9/2013

Clinical Orthopaedics and Related Research® 9/2013 Go to the issue

Clinical Research

Total Hip Arthroplasty for the Sequelae of Legg-Calvé-Perthes Disease

Symposium: Tscherne Festschrift

Submuscular Bridge Plating for Complex Pediatric Femur Fractures Is Reliable

Survey

Is Lateral Pin Fixation for Displaced Supracondylar Fractures of the Humerus Better Than Crossed Pins in Children?

Symposium: Tscherne Festschrift

Is the Transplant Quality at the Time of Surgery Adequate for Matrix-guided Autologous Cartilage Transplantation? A Pilot Study

CORR Insights®

CORR Insights®: The Peripheral Neuronal Phenotype is Important in the Pathogenesis of Painful Human Tendinopathy: A Systematic Review

Symposium: Tscherne Festschrift

Is There a Difference in Timing and Cause of Death After Fractures in the Elderly?