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Isolation of Endothelial Progenitor Cells from Healthy Volunteers and Their Migratory Potential Influenced by Serum Samples After Cardiac Surgery

Endothelial progenitor cells (EPCs) are recruited from the bone marrow under pathological conditions like hypoxia and are crucially involved in the ...

University Hospital Aachen

Key role of MIF in the migration of endothelial progenitor cells in patients during cardiac surgery.

Emerging evidence suggests a pivotal role of macrophage migration inhibitory factor (MIF) in the systemic inflammatory immune response. MIF is located in various cell types and rapidly released after different stimuli like inflammation, surgical stress or ischemia and reperfusion. MIF is a known key player in the inflammatory response and contributes to several biological functions including the control of cell cycle (through activation of ERK1/2), sensing of pathogen stimuli (upregulation of TLR4 expression), recruitment of various immune cells (neutrophils, monocytes) and prevention of p53-mediated apoptosis of macrophages. While MIF`s pro-inflammatory effects are crucial for an effective host defense, elevated MIF levels were repeatedly shown to be associated with the development of organ dysfunction and deleterious sequelae. Even more puzzling, increasing evidence indicates a protective role of this pleiotropic cytokine during ischemia and reperfusion injury in the myocardium. This review focuses on new insights regarding the biological significance of MIF release in the context of critical illness and ischemia/ reperfusion.

The role of macrophage migration inhibitory factor in critical illness.

Cardiac surgery involves myocardial ischemia/reperfusion (I/R) with potentially deleterious consequences. Macrophage migration inhibitory factor (MIF) is a stress-regulating chemokine-like cytokine that protects against I/R damage, but functional links with its homolog, d-dopachrome tautomerase (MIF-2), and the circulating soluble receptor CD74 (sCD74) are unknown. In this study, we investigate the role of MIF, MIF-2, sCD74, and MIF genotypes in patients scheduled for elective single or complex surgical procedures such as coronary artery bypass grafting or valve replacement.

Interaction of MIF Family Proteins in Myocardial Ischemia/Reperfusion Damage and Their Influence on Clinical Outcome of Cardiac Surgery Patients.

Cardiac surgery encompasses various stimuli that trigger pro-inflammatory mediators, reactive oxygen species and mobilization of leucocytes. The aim of this study was to evaluate the effect of xenon on the inflammatory response during cardiac surgery.

Xenon triggers pro-inflammatory effects and suppresses the anti-inflammatory response compared to sevoflurane in patients undergoing cardiac surgery.

The chemokine CXCL16 and its receptor CXCR6 have been linked to the pathogenesis of acute and chronic cardiovascular disease. However, data on the clinical significance of CXCL16 in patients undergoing cardiac surgery with acute myocardial ischemia/reperfusion (I/R) are still lacking. Therefore, we determined CXCL16 in the serum of cardiac surgery patients and investigated its kinetics and association with the extent of organ dysfunction. 48 patients underwent conventional cardiac surgery with myocardial I/R and the use of cardiopulmonary bypass (CPB) were consecutively enrolled in the present study. We investigated the peri- and post-operative profile of CXCL16. Clinical relevant data were assessed and documented throughout the entire observation period. To identify the influence of myocardial I/R and CPB on CXCL16 release data were compared to those received from patients that underwent off-pump procedure. Pre-operative serum CXCL16 levels were comparable to those obtained from healthy volunteers (1174 ± 55.64 pg/ml versus 1225 ± 70.94). However, CXCL16 levels significantly increased during surgery (1174 ± 55.64 versus 1442 ± 75.42 pg/ml; P = 0.0057) and reached maximum levels 6 hrs after termination of surgery (1174 ± 55.64 versus 1648 ± 74.71 pg/ml; P < 0.001). We revealed a positive correlation between the intraoperative serum levels of CXCL16 and the extent of organ dysfunction (r(2) = 0.356; P = 0.031). Patients with high CXCL16 release showed an increased extent of organ dysfunction compared to patients with low CXCL16 release. Our study shows that CXCL16 is released into the circulation as a result of cardiac surgery and that high post-operative CXCL16 levels are associated with an increased severity of post-operative organ dysfunctions.

The perioperative time course and clinical significance of the chemokine CXCL16 in patients undergoing cardiac surgery.

The licensed anesthetic xenon, which exerts organ protective properties, was recently added by the World Anti-Doping Agency to the list of prohibited substances. Xenon is supposed to trigger the production of hypoxia-inducible factor 1α (HIF-1α) and subsequently erythropoietin, but data are limited to in vivo experimental work. Therefore we evaluated the effect of xenon on erythropoietin levels in healthy persons.

Sub-anesthetic Xenon Increases Erythropoietin Levels in Humans: A Randomized Controlled Trial.

In the present observational study, we measured serum levels of the chemokine stromal cell-derived factor-1α (SDF-1α) in 100 patients undergoing cardiac surgery with cardiopulmonary bypass at seven distinct time points including preoperative values, myocardial ischemia, reperfusion, and the postoperative course. Myocardial ischemia triggered a marked increase of SDF-1α serum levels whereas cardiac reperfusion had no significant influence. Perioperative SDF-1α serum levels were influenced by patients' characteristics (e.g., age, gender, aspirin intake). In an explorative analysis, we observed an inverse association between SDF-1α serum levels and the incidence of organ dysfunction. In conclusion, time of myocardial ischemia was identified as the key stimulus for a significant upregulation of SDF-1α, indicating its role as a marker of myocardial injury. The inverse association between SDF-1α levels and organ dysfunction association encourages further studies to evaluate its organoprotective properties in cardiac surgery patients.

Myocardial Ischemia Induces SDF-1α Release in Cardiac Surgery Patients.

We hypothesized that cluster of differentiation 74 (CD74) downregulation on placental macrophages, leading to altered macrophage-trophoblast interaction, is involved in preeclampsia.

Article	Year
Key role of MIF in the migration of endothelial progenitor cells in patients during cardiac surgery. International journal of cardiology\| PubMed ID: 25535692	2015
The role of macrophage migration inhibitory factor in critical illness. Mini reviews in medicinal chemistry\| PubMed ID: 25643612	2014
Interaction of MIF Family Proteins in Myocardial Ischemia/Reperfusion Damage and Their Influence on Clinical Outcome of Cardiac Surgery Patients. Antioxidants & redox signaling\| PubMed ID: 26234719	2015
Xenon triggers pro-inflammatory effects and suppresses the anti-inflammatory response compared to sevoflurane in patients undergoing cardiac surgery. Critical care (London, England)\| PubMed ID: 26467531	2015
The perioperative time course and clinical significance of the chemokine CXCL16 in patients undergoing cardiac surgery. Journal of cellular and molecular medicine\| PubMed ID: 26499307	2016
Sub-anesthetic Xenon Increases Erythropoietin Levels in Humans: A Randomized Controlled Trial. Sports medicine (Auckland, N.Z.)\| PubMed ID: 26939898	2016
Myocardial Ischemia Induces SDF-1α Release in Cardiac Surgery Patients. Journal of cardiovascular translational research\| PubMed ID: 27055858	2016
CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia. Circulation research\| PubMed ID: 27199465	2016

Christoph Emontzpohl

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