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High Macrophage Migration Inhibitory Factor Levels in Disseminated Intravascular Coagulation Patients with Systemic Inflammation

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Abstract

To determine the relationship between macrophage migration inhibitory factor (MIF) and disseminated intravascular coagulation (DIC) in patients with systemic inflammatory response syndrome (SIRS) and sepsis, and their relationship to multiple organ dysfunction syndrome (MODS) and prognosis, we conducted a prospective cohort study. Forty-eight patients with SIRS or sepsis were classified as 20 DIC and 28 non-DIC patients. MIF, tumor necrosis factor-alpha (TNF-alpha), soluble fibrin, protein C activity (protein C), and plasminogen activator inhibitor-1 (PAI-1) were all measured within 24 h after the patients met the criteria of SIRS or sepsis (day 0), and on days 1 to 4. The number of SIRS criteria that the patients met and the DIC scores were determined simultaneously. In DIC patients, significantly higher levels of MIF, TNF-alpha, soluble fibrin, PAI-1 were found compared with non-DIC patients. We also found significantly lower protein C levels in the DIC patients than in the non-DIC patients. Significant correlations were found between the peak levels of MIF and soluble fibrin in the DIC patients (rs = 0.496, p < 0.0407). All DIC patients had MODS and also showed a higher number of dysfunctioning organs and a poorer prognosis than the non-DIC patients. A simple logistic regression analysis showed the peak MIF levels and DIC significantly to be related to the patients’ death (odds ratio 1.016 and 40.5; p < 0.0409, p < 0.0009, respectively). In conclusion, DIC patients with elevated levels of MIF and TNF-alpha had more organ dysfunctions leading to a poor prognosis in a population of SIRS and sepsis patients. MIF may therefore play a role in the inflammatory and thrombotic processes in DIC patients.

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References

  1. Calandra, T., J. Bernhagen, C. N. Metz, L. A. Spiegel, M. Bacher, T. Donnelly, A. Cerami, and R. Bucala. 1995. MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377:68–71.

    Article  PubMed  CAS  Google Scholar 

  2. Bucala, R., and MIF rediscovered. 1996. Cytokine, pituitary hormone, and glucocorticoid-induced regulator of the immune response. FASEB J. 10:1607–1613.

    PubMed  CAS  Google Scholar 

  3. Calandra, T., and T. Roger. 2003. Macrophage migration inhibitory factor. A regulator of innate immunity. Nature Rev. 3:791–800.

    Article  CAS  Google Scholar 

  4. Members of American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. 1992. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit. Care Med. 20:864–874.

    Article  Google Scholar 

  5. Bernhagen, J., T. Calandra, R. A. Mitchell, S. B. Martin, K. J. Tracey, W. Voelter, K. R. Manogue, A. Cerami, and R. Bucala. 1993. MIF is a pituitary-derived cytokine that potentiates lethal endotoxemia. Nature 365:756–759.

    Article  PubMed  CAS  Google Scholar 

  6. Bozza, M., A. R. Satoskar, G. Lin, B. Lu, A. A. Humbles, C. Gerard, and J. R. David. 1999. Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J. Exp. Med. 189:341–346.

    Article  PubMed  CAS  Google Scholar 

  7. Calandra, T., B. Echtenacher, D. L. Roy, J. Pugin, C. N. Metz, L. Hültner, D. Heumann, D. Männel, R. Bucala, and M. P. Glauser. 2000. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nature Med. 6:164–170.

    Article  PubMed  CAS  Google Scholar 

  8. Gando, S., J. Nishihira, S. Kobayashi, Y. Morimoto, S. Nanzaki, and O. Kemmotsu. 2001. Macrophage migration inhibitory factor is a critical mediator of systemic inflammatory response syndrome. Intensive Care Med. 27:1187–1193.

    Article  PubMed  CAS  Google Scholar 

  9. Lehmann, L. E., U. Novender, S. Schroeder, T. Pietsch, C. Putensen, A. Hoeft, and F. Stüber. 2001. Plasma levels of macrophage migration inhibitory factor are elevated in patients with severe sepsis. Intensive Care Med. 27:1412–1415.

    Article  PubMed  CAS  Google Scholar 

  10. Beishuizen, A., L. G. Thijs, C. Haanen, and I. Vermes. 2001. Macrophage migration inhibitory factor and hypothalamo-pituitary-adrenal function during critical illness. J. Clin. Endocrinol. Metab. 86:2811–2816.

    Article  PubMed  CAS  Google Scholar 

  11. Bozza, F., R. N. Gomes, A. M. Japiassu, M. Soares, H. C. Castro-Faria-Neto, P. T. Bozza, and M. T. Bozza. 2004. Marophage migration inhibitory factor levels correlate with fatal outcome in sepsis. Shock 22:309–313.

    Article  PubMed  CAS  Google Scholar 

  12. Esmon, C. T. 2003. Inflammation and thrombosis. J. Thromb. Haemost. 1:1343–1348.

    Article  PubMed  CAS  Google Scholar 

  13. Nishihira, J., Y. Mizue, and W. Sakamoto. 1999. Induction of T-kininogen and tumor necrosis factor-alpha by macrophage migration inhibitory factor in vivo. Semin. Thromb. Haemost. 25:557–562.

    CAS  Google Scholar 

  14. Shimizu, T., J. Nishihira, H. Watanabe, R. Abe, A. Honda, T. Ishibashi, and H. Shimizu. 2004. Macrophage migration inhibitory factor is induced by thrombin and factor Xa in endothelial cells. J. Biol. Chem. 279:13729–13737.

    Article  PubMed  CAS  Google Scholar 

  15. Knaus, W. A., E. A. Draper, D. P. Wanger, and J. E. Zimmerman. 1985. APACHE II: a severity classification system. Crit. Care Med. 13:818–829.

    Article  PubMed  CAS  Google Scholar 

  16. Murray, J. F., M. A. Matthay, J. M. Luce, and M. R. Flick. 1988. An expanded definition of the adult respiratory distress syndrome. Am. Rev. Respir. Dis. 138:720–723.

    PubMed  CAS  Google Scholar 

  17. Gando, S., T. Kameue, S. Nanzaki, and Y. Nakanishi. 1996. Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome. Thromb. Haemost. 75:224–228.

    Article  PubMed  CAS  Google Scholar 

  18. Taylor, F. B. Jr., C. H. Toh, W. K. Hoots, H. Wada, and M. Levi. 2001. Toward definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb. Haemost. 86:1327–1330.

    PubMed  CAS  Google Scholar 

  19. Onodera, S., K. Suzuki, K. Kaneda, M. Fuinaga, and J. Nishihira. 1999. Growth factor-induced expression of macrophage migration inhibitory factor in osteoblasts: relevance to the plasminogen activator system. Semin. Thromb. Haemost. 25:563–567.

    Article  CAS  Google Scholar 

  20. Schmidt-Supprian, M., C. Murphy, B. While, M. Lawler, A. Kapurniotu, W. Voelter, O. Smith, and J. Bernhagen. 2000. Activated protein C inhibits tumor necrosis factor and macrophage migration inhibitory factor production in monocytes. Eur. Cytokine. Netw. 11:407–413.

    PubMed  CAS  Google Scholar 

  21. Hamano, S., S. Tanaka, Y. Takeda, M. Umeda, and Y. Sakata. 2002. A novel monoclonal antibody to fibrin monomer and soluble fibrin for the detection of soluble fibrin in plasma. Clin. Chim. Acta 318:25–32.

    Article  PubMed  CAS  Google Scholar 

  22. Levi, M., and H. ten Cate. 1999. Disseminated intravascular coagulation. N. Engl. J. Med. 341:586–592.

    Article  PubMed  CAS  Google Scholar 

  23. Furukawa, M. 2004. Anti-MIF monoclonal antibody inhibits LPS-stimulated expression of tissue factor. Hokkaido Medical Journal. 79: 523–532. (In Japanese).

    Google Scholar 

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Acknowledgements

We thank Miss Y. Mizue of Sapporo Immunodiagnostic Laboratories for assistance in measuring the MIF. This work was supported in part by a Grant-in Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (2002-14657379).

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Correspondence to Satoshi Gando.

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Gando, S., Sawamura, A., Hayakawa, M. et al. High Macrophage Migration Inhibitory Factor Levels in Disseminated Intravascular Coagulation Patients with Systemic Inflammation. Inflammation 30, 118–124 (2007). https://doi.org/10.1007/s10753-007-9027-1

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