Elsevier

Journal of Surgical Research

Volume 164, Issue 1, November 2010, Pages e163-e171
Journal of Surgical Research

Shock/Sepsis/Trauma/Critical Care
Macrophage Migration Inhibitory Factor (MIF) and Manganese Superoxide Dismutase (MnSOD) as Early Predictors for Survival in Patients with Severe Sepsis or Septic Shock

https://doi.org/10.1016/j.jss.2010.05.004Get rights and content

Background

Severe sepsis, septic shock, and resulting organ failure appear as the most common cause of death in intensive care medicine. Inflammatory mediators (interleukin-6/IL-6), cell adhesion molecules (intercellular adhesion molecule-1/ICAM-1, vascular cell adhesion molecule-1/VCAM-1), and redox active substances (manganese superoxide dismutase/MnSOD, macrophage migration inhibitory factor/MIF) must be considered to be central hubs in the inflammatory process. However, their exact pathophysiologic function and prognostic value are still poorly understood.

Materials and Methods

In total, 133 individuals (87 patients with severe sepsis or septic shock, 28 postoperative patients after major abdominal surgery, 18 healthy volunteers) were enrolled in the study. Blood samples from septic patients were collected within 24 h after the time of sepsis diagnosis, and 48 and 120 h later; samples from healthy volunteers were collected once, and samples from postoperative patients once immediately after surgery. In all patients we measured plasma levels of IL-6, sICAM-1, sVCAM-1, MnSOD, and MIF using enzyme linked immunosorbent assay (ELISA) kits.

Results

Healthy volunteers and postoperative patients showed comparable levels of cell adhesion molecules. Furthermore, their redox system was activated in a comparable manner, whereas in postoperative patients IL-6 was significantly elevated. Plasma levels of inflammatory mediators, cell adhesion molecules and redox active substances were significantly elevated in septic patients. In patients with sepsis who had died, plasma levels of MIF and MnSOD were significantly elevated in comparison with survivors.

Conclusions

Our results therefore demonstrate that redox active substances may play an important role in the septic inflammatory response. MIF and MnSOD appear to be early predictors for survival in septic patients.

Introduction

Severe sepsis, septic shock, and the resulting multiple organ failure/dysfunction syndrome represent an ongoing challenge in intensive care units 1, 2, 3, 4, 5. With mortality ranging from 40% to 70%, septic shock is the most common cause of death in intensive care medicine 2, 6. Despite intensive basic research and clinical studies, the pathophysiology of sepsis is still poorly understood. Sepsis is a heterogeneous, dynamic syndrome caused by imbalances in the inflammatory network. Many different mediators are involved in the pathology of sepsis, some of which (e.g., interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), manganese superoxide dismutase (MnSOD), macrophage migration inhibitory factor (MIF) may be considered to be central hubs in the inflammatory process. IL-6 is the most commonly described cytokine after surgery 7, 8, 9, 10. Furthermore IL-6 appears to be a good marker of the severity of infection 11, 12. ICAM-1 and VCAM-1 are inducible glycoproteins that are expressed during inflammatory reactions. The up-regulation on the surface of endothelial cells mediates stable leucocyte adhesion to the vascular endothelium. This process leads to leucocyte extravasation into sites of infection or injury and, therefore, plays a pivotal role in the development of organ injury in sepsis [13]. The soluble forms of vascular cell adhesion molecule (sVCAM)-1 and intercellular adhesion molecule (sICAM)-1 represent reliable markers for immune activation and response. High levels of adhesion molecules have been found in different stages of disease, especially inflammation and infection 14, 15, 16, 17, 18, 19. MnSOD is an inducible antioxidant enzyme that is located in the mitochondria and protects against oxidative damage caused by reactive oxygen species. It catalyzes the dismutation of superoxide radicals to oxygen and hydrogen peroxide and has been shown to play an important role in mediating protection against lipopolysaccharide (LPS) and other oxidative events 20, 21, 22. MIF functions as a classic pro-inflammatory cytokine and promotes innate and adaptive immune response by activating T-cells and macrophages [23]. For the acute phase of sepsis, it has been demonstrated that high plasma levels are harmful and correlate with sepsis severity [24]. The neutralization of MIF resulted in an attenuation of the inflammatory response and improved survival in experimental sepsis 24, 25.

Therefore, IL-6, (s)ICAM-1, (s)VCAM-1, MnSOD, and MIF are considered to be central hubs in the inflammatory response. All these factors do have one common characteristic: they are either involved in the regulation of NFκB (e.g., MIF), or are themselves regulated by a NFκB dependant pathway (e.g., MnSOD). NFκB is an inducible transcription factor that plays an essential role in the expression of a number of genes involved in inflammatory processes, apoptosis, and intracellular redox-related processes 26, 27, 28, 29, 30, 31, 32. However, no sufficient knowledge exists about the prognostic value of these key mediators in severe sepsis. The aims of this study were therefore 2-fold: (1) to assess the plasma level of each parameter in different inflammatory settings (healthy volunteers, postoperative, and septic patients) and (2) to investigate the prognostic value of each parameter in septic patients.

Section snippets

Materials and Methods

The observational clinical study was approved by the local ethics committee and was conducted in the surgical and medical intensive care units of the University Hospitals of Heidelberg and Mannheim, Germany. All study and control patients or their legal designees signed written informed consent. In total, 133 individuals in three groups were enrolled in the study. The three groups included 87 patients with severe sepsis or septic shock (referred to as the septic group), 28 patients after major

Results

Age and gender of patients in the septic and postoperative groups were comparable (Table 1). In the septic group, patients who survived or died showed no significant differences concerning their demographic data (data not shown). In contrast, healthy volunteers were significantly younger compared with the septic and postoperative groups (Table 1).

The primary site of infection in the septic group was the respiratory tract (51 patients, 58.6%), followed by the genitourinary tract (nine patients,

Discussion

The present study demonstrates that Macrophage Migration Inhibitory Factor (MIF) and Manganese Superoxide Dismutase (MnSOD) may function as early predictors for survival in patients with severe sepsis or septic shock.

Severe sepsis, septic shock, and related multiple organ dysfunction syndrome is still the most common cause of death in intensive care medicine 1, 2, 3, 4, 5, 6. Many of the pathophysiologic changes during sepsis are related to inflammation [37]. The failure to control inflammation

Conclusions

In summary, we have demonstrated that inflammatory markers (e.g. IL-6), cell adhesion molecules (e.g. sICAM-1, sVCAM-1) and mediators involved in the redox homeostasis (e.g., MnSOD, MIF) may represent central hubs in the septic inflammatory response. The plasma level measurements of MIF and MnSOD in septic patients appear to be an early predictor for survival in patients with severe sepsis or septic shock.

Acknowledgments

The authors thank U. Krauser and C. Liebetrau for their excellent technical assistance. This study was carried out with financial resources of the Department of Anesthesiology (University of Heidelberg, Germany), the Department of Surgery (University of Heidelberg, Germany), the First Department of Medicine (Faculty of Medicine, University of Mannheim, Germany), and the Institute of Medical Biometry and Informatics (University of Heidelberg, Germany). This research received no specific grant

References (55)

  • A. Mitsui et al.

    Reactive oxygen-reducing and protein-refolding activities of adult T cell leukemia-derived factor/human thioredoxin

    Biochem Biophys Res Commun

    (1992)
  • C. Alberti et al.

    Influence of systemic inflammatory response syndrome and sepsis on outcome of critically ill infected patients

    Am J Respir Crit Care Med

    (2003)
  • D. Annane et al.

    Current epidemiology of septic shock: The CUB-Rea Network

    Am J Respir Crit Care Med

    (2003)
  • C. Brun-Buisson et al.

    Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis

    JAMA

    (1995)
  • C. Brun-Buisson et al.

    EPISEPSIS: A reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units

    Intensive Care Med

    (2004)
  • G.S. Martin et al.

    The epidemiology of sepsis in the United States from 1979 through 2000

    N Engl J Med

    (2003)
  • D.C. Angus et al.

    Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care

    Crit Care Med

    (2001)
  • E.A. Deitch et al.

    Role of the gut in the development of injury- and shock induced SIRS and MODS: The gut-lymph hypothesis, a review

    Front Biosci

    (2006)
  • K. Fassbender et al.

    Interleukin-6 and acute-phase protein concentrations in surgical intensive care unit patients: Diagnostic signs in nosocomial infection

    Crit Care Med

    (1993)
  • J. Van Snick

    Interleukin-6: An overview

    Annu Rev Immunol

    (1990)
  • P. Damas et al.

    Cytokine serum level during severe sepsis in human IL-6 as a marker of severity

    Ann Surg

    (1992)
  • J.E. Parrillo

    Pathogenetic mechanisms of septic shock

    N Engl J Med

    (1993)
  • P.L. Ramsay et al.

    Early clinical markers for the development of bronchopulmonary dysplasia: Soluble E-Selectin and ICAM-1

    Pediatrics

    (1998)
  • R. Austgulen et al.

    Infections in neonates delivered at term are associated with increased serum levels of ICAM-1 and E-selectin

    Acta Paediatr

    (1997)
  • S. Endo et al.

    Levels of soluble adhesion molecules and cytokines in patients with septic multiple organ failure

    J Inflamm

    (1995)
  • M. Xanthou et al.

    Inflammatory mediators in perinatal asphyxia and infection

    Acta Paediatr Suppl

    (2002)
  • L.B. Clerch et al.

    Tolerance of rats to hyperoxia. Lung antioxidant enzyme gene expression

    J Clin Invest

    (1993)
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