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Fracture initiates systemic inflammatory response syndrome through recruiting polymorphonuclear leucocytes

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Abstract

Fracture, a common type injury in trauma patients, often results in the development of the systemic inflammatory response syndrome (SIRS). Though the mechanism of the fracture-initiated SIRS still remains not well characterized, it is well documented that the polymorphonuclear leucocytes (PMN) play an important role in the inflammatory process. We hypothesize that fractures recruit PMN to the local tissue, which is followed by an increase in the number of peripheral PMN and initiation of SIRS. In the current study, we established a closed femoral fracture rat model. We evaluated the levels of MPO, IL-1β and CINC-1 in fractured tissue homogenate, and we measured the levels of IL-6 and IL-10, the biomarkers for systemic inflammatory response, in the rat sera. In clinical part of the study, we collected blood from patients with isolated closed femoral fractures and evaluated PMN-related chemoattractants (IL-8, IL-1β and G-CSF) and the number of peripheral PMN. We further evaluated the level of mitochondrial DNA in the local haematoma of fracture and the circulating plasma of the patients with fracture. In the animal model of closed femoral fracture, we found a significant recruitment of PMN to the local tissue after fracture, which correlates with the elevated MPO level. We also showed that the concentration of IL-1β and CINC-1 in local tissue is significantly increased and might be responsible for the PMN recruitment. Recruitment of PMN to the local tissue was accompanied with a significant increase in the systemic levels of IL-6 and IL-10 in serum. In the patients with closed femoral fracture, we observed an increase in the number of peripheral PMN and PMN-related chemoattractants, including IL-8, IL-1β and G-CSF. The level of mitochondrial DNA in the local haematoma of fracture and the circulating plasma of patients were significantly higher compared to the healthy volunteers. Our data suggest that fracture released mitochondrial DNA into the local haematoma of fracture, which recruited the PMN into the local tissue via chemokines (IL-1β and CINC-1), then increased the numbers of peripheral PMN and SIRS related cytokines in serum (IL-6 and IL-10). This might be the mechanism of the fracture-initiated SIRS.

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References

  1. Weckbach S, Perl M, Heiland T, Braumüller S, Stahel PF, Flierl MA, Ignatius A, Gebhard F, Huber-Lang M. A new experimental polytrauma model in rats: molecular characterization of the early inflammatory response. Mediat Inflamm. 2012;2012:890816.

    Article  Google Scholar 

  2. 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(2):e149–56.

    Article  PubMed  Google Scholar 

  3. Balogh ZJ, Reumann MK, Gruen RL, Mayer-Kuckuk P, Schuetz MA, Harris IA, Gabbe BJ, Bhandari M. Advances and future directions for management of trauma patients with musculoskeletal injuries. Lancet. 2012;380(9847):1109–19.

    Article  PubMed  Google Scholar 

  4. Kobbe P, Vodovotz Y, Kaczorowski DJ, Mollen KP, Billiar TR, Pape HC. Patterns of cytokine release and evolution of remote organ dysfunction after bilateral femur fracture. Shock. 2008;30(1):43–7.

    Article  CAS  PubMed  Google Scholar 

  5. Pfeifer R, Kobbe P, Darwiche SS, 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(2):270–4.

    Article  PubMed  Google Scholar 

  6. Kobbe P, Kaczorowski DJ, Vodovotz Y, Tzioupis CH, Mollen KP, Billiar TR, Pape HC. Local exposure of bone components to injured tissue induces Toll-like receptor 4-dependent systemic inflammation with acute lung injury. Shock. 2008;30(6):686–91.

    Article  CAS  PubMed  Google Scholar 

  7. Segel GB, Halterman MW, Lichtman MA. The paradox of the neutrophil’s role in tissue injury. J Leukoc Biol. 2011;89(3):359–72.

    Article  CAS  PubMed  Google Scholar 

  8. Bastian O, Pillay J, Alblas J, Leenen L, Koenderman L, Blokhuis T. Systemic inflammation and fracture healing. J Leukoc Biol. 2011;89(5):669–73. doi:10.1189/jlb.0810446 Epub 2011 Jan 4.

    Article  CAS  PubMed  Google Scholar 

  9. Hsu LC, Enzler T, Seita J, Timmer AM, Lee CY, Lai TY, Yu GY, Lai LC, Temkin V, Sinzig U, Aung T, Nizet V, Weissman IL, Karin M. IL-1β-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKβ. Nat Immunol. 2011;12(2):144–50.

    Article  CAS  PubMed  Google Scholar 

  10. Beck-Schimmer B, Schwendener R, Pasch T, Reyes L, Booy C, Schimmer RC. Alveolar macrophages regulate neutrophil recruitment in endotoxin-induced lung injury. Respir Res. 2005;22(6):61.

    Article  Google Scholar 

  11. Chandrasekar B, Smith JB, Freeman GL. Ischemia-reperfusion of rat myocardium activates nuclear factor-KappaB and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemokine. Circulation. 2001;103(18):2296–302.

    Article  CAS  PubMed  Google Scholar 

  12. Lee PY, Kumagai Y, Xu Y, Li Y, Barker T, Liu C, Sobel ES, Takeuchi O, Akira S, Satoh M, Reeves WH. IL-1α modulates neutrophil recruitment in chronic inflammation induced by hydrocarbon oil. J Immunol. 2011;186(3):1747–54.

    Article  CAS  PubMed  Google Scholar 

  13. Hoth JJ, Wells JD, Hiltbold EM, McCall CE, Yoza BK. Mechanism of neutrophil recruitment to the lung after pulmonary contusion. Shock. 2011;35(6):604–9.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bae GH, Lee HY, Jung YS, Shim JW, Kim SD, Baek SH, Kwon JY, Park JS, Bae YS. Identification of novel peptides that stimulate human neutrophils. Exp Mol Med. 2012;44(2):130–7.

    Article  CAS  PubMed  Google Scholar 

  15. Hauser CJ, Sursal T, Rodriguez EK, Appleton PT, Zhang Q, Itagaki K. Mitochondrial damage associated molecular patterns from femoral reamings activate neutrophils through formyl peptide receptors and P44/42 MAP kinase. J Orthop Trauma. 2010;24(9):534–8.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285):104–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang H, Sun T, Liu Z, Zhang J, Wang X, Liu J. Systemic inflammatory responses and lung injury following hip fracture surgery increases susceptibility to infection in aged rats. Mediat Inflamm. 2013;2013:536435.

    Google Scholar 

  18. Heling Dai, Tiansheng Sun, Zhi Liu, Jianzheng Zhang, Meng Zhou. The imbalance between regulatory and IL-17-secreting CD4+ T cells in multiple-trauma rat. Injury. 2013;44(11):1521–7.

    Article  Google Scholar 

  19. McDonald MM, Morse A, Peacock L, Mikulec K, Schindeler A, Little DG. Characterization of the bone phenotype and fracture repair in osteopetrotic incisors absent rats. J Orthop Res. 2011;29(5):726–33.

    Article  PubMed  Google Scholar 

  20. Zhao C, Itagaki K, Gupta A, Odom S, Sandler N, Hauser CJ. Mitochondrial damage-associated molecular patterns released by abdominal trauma suppress pulmonary immune responses. J Trauma Acute Care Surg. 2014;76(5):1222–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hietbrink F, Koenderman L, Leenen LP. Intramedullary nailing of the femur and the systemic activation of monocytes and neutrophils. World J Emerg Surg. 2011;31(6):34.

    Article  Google Scholar 

  22. Hofer HP, Egger G, Kukovetz EM, Bratschitsch G, Steindorfer P, Schaur RJ. The influence of trauma on changes in neutrophil granulocyte function assessed by an analysis of granulocyte migration. Langenbecks Arch Chir. 1996;381(3):148–54.

    Article  CAS  PubMed  Google Scholar 

  23. Amanzada A, Malik IA, Nischwitz M, Sultan S, Naz N, Ramadori G. Myeloperoxidase and elastase are only expressed by neutrophils in normal and in inflamed liver. Histochem Cell Biol. 2011;135(3):305–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sears BW, Volkmer D, Yong S, Himes RD, Lauing K, Morgan M, Stover MD, Callaci JJ. Correlation of measurable serum markers of inflammation with lung levels following bilateral femur fracture in a rat model. J Inflamm Res. 2010;3:105–14.

    Article  CAS  PubMed Central  Google Scholar 

  25. Pulli B, Ali M, Forghani R, Schob S, Hsieh KL, Wojtkiewicz G, Linnoila JJ, Chen JW. Measuring myeloperoxidase activity in biological samples. PLoS ONE. 2013;8(7):e67976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Johnson EA, Dao TL, Guignet MA, Geddes CE, Koemeter-Cox AI, Kan RK. Increased expression of the chemokines CXCL1 and MIP-1α by resident brain cells precedes neutrophil infiltration in the brain following prolonged soman-induced status epilepticus in rats. J Neuroinflammation. 2011;2(8):41.

    Article  Google Scholar 

  27. Karmakar M, Sun Y, Hise AG, Rietsch A, Pearlman E. Cutting edge: IL-1β processing during Pseudomonas aeruginosa infection is mediated by neutrophil serine proteases and is independent of NLRC4 and caspase-1. J Immunol. 2012;189(9):4231–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Borregaard N. Neutrophils, from marrow to microbes. Immunity. 2010;33(5):657–70.

    Article  CAS  PubMed  Google Scholar 

  29. Sadik CD, Kim ND, Luster AD. Neutrophils cascading their way to inflammation. Trends Immunol. 2011;32(10):452–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011;11(8):519–31.

    Article  CAS  PubMed  Google Scholar 

  31. Kobayashi SD, Voyich JM, Burlak C, DeLeo FR. Neutrophils in the innate immune response. Arch Immunol Ther Exp (Warsz). 2005;53(6):505–17.

    CAS  Google Scholar 

  32. Mommsen P, Barkhausen T, Frink M, Zeckey C, Probst C, Krettek C, Hildebrand F. Productive capacity of alveolar macrophages and pulmonary organ damage after femoral fracture and hemorrhage in IL-6 knockout mice. Cytokine. 2011;53(1):60–5.

    Article  CAS  PubMed  Google Scholar 

  33. Volpin G, Cohen M, Assaf M, et al. Cytokine levels (IL-4, IL-6, IL-8 and TGFβ) as potential biomarkers of systemic inflammatory response in trauma patients. Int Orthop. 2014;38(6):1303–9.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Beijing Army General Hospital, Nanmencang No. 5, Dongcheng District, Beijing, 100700, China

    Haipeng Li, Jia Liu, Jianhua Yao, Jianfeng Zhong, Lei Guo & Tiansheng Sun

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  1. Haipeng Li
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  2. Jia Liu
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  3. Jianhua Yao
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Correspondence to Tiansheng Sun.

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Li, H., Liu, J., Yao, J. et al. Fracture initiates systemic inflammatory response syndrome through recruiting polymorphonuclear leucocytes. Immunol Res 64, 1053–1059 (2016). https://doi.org/10.1007/s12026-016-8801-2

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