Shock/Sepsis/Trauma/Critical CareMacrophage Migration Inhibitory Factor (MIF) and Manganese Superoxide Dismutase (MnSOD) as Early Predictors for Survival in Patients with Severe Sepsis or Septic Shock
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
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Biomarkers of sepsis
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2021, Journal of EthnopharmacologyCitation Excerpt :Inflammation leads to oxidative stress because of the production of reactive oxygen species (ROS), including malondialdehyde (MDA) and myeloperoxidase (MPO). Therefore, to avoid the harmful effects of excessive ROS production, immune cells must produce adequate amounts of anti-oxidants, such as superoxide dismutase (SOD) and glutathione peroxidase (GSH) (Brenner et al., 2010). Chen et al. (2011) found that XBJ treatment might ameliorate sepsis-induced lung injury by reducing the expression of MDA and MPO and the serum levels of TNF-α.
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2018, Free Radical Biology and MedicineCitation Excerpt :In addition, damage to mitochondria from oxidative stress appears to be fundamental to the pathophysiology of organ failure and death in sepsis [3–6]. Experimental and clinical studies evaluated the association of SOD and sepsis [27–31]. Macarthur et al. showed in Sprague-Dawley rats that, postinfection treatment with the superoxide dismutase mimetic, protects against hypotension, vascular hyporeactivity to catecholamines, and mortality associated with septic shock [28].
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2018, Journal of Critical CareCitation Excerpt :Distinguishing patients that are progressing into severe sepsis from those with uncomplicated sepsis is essential because it determines early treatment strategies in the ED and to predict the patient's prognosis. Previous studies showed that the measurement of one immunological/inflammatory biomarker at a time has minimal to no value [7-10]; nevertheless, assessment of a group of biomarkers is likely to provide a more accurate prediction of the disease severity [11-14]. A previous study validating a tool to stratify sepsis risks discovered that assessment of lactate concentration at admission, age, presence of chronic diseases, and level of five biomarkers were critical to evaluate the susceptibility to sepsis-associated death in adult patients [15].
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2018, CytokineCitation Excerpt :It is secreted by both immune cells (such as macrophages and T cells) and organ specific cells (such as hepatocytes and osteoblasts), and unlike other cytokines, it is also secreted by the pituitary gland in response to infection [4]. Interest in MIF has expanded since its discovery in 1966 [5] and it has been implicated in a range of acute and chronic inflammatory conditions [6–9]. For this reason, MIF has been frequently proposed as a potential disease biomarker [7–11].
- 2
These authors contributed equally, each as first author of this work and in preparing the original research paper.
- 3
These authors share senior authorship.