Myocardial ischemia/reperfusion injury: inflammatory mechanisms, endothelial progenitor cells and preconditioning modification by anesthetics

Emontzpohl, Christoph; Bernhagen, J├╝rgen (Thesis advisor); Stoppe, Christian (Thesis advisor); Bohrmann, Johannes (Thesis advisor)

Aachen (2019)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2019


Myocardial ischemia/reperfusion (I/R) during a cardiac surgical intervention leads to a subsequent inflammatory response, whereas the exact underlying mechanisms are not yet fully understood. The aim of this study was to evaluate the impact of myocardial I/R during a cardiac surgical intervention on the inflammatory response in patients with coronary heart disease, and to evaluate the release of the pro-inflammatory chemokine-like function cytokine macrophage migration inhibitory factor (MIF) and its influence on the migration of endothelial progenitor cells (EPC) as crucial pro-angiogenic factor. The aim of the second part of this study was to investigate the influence of anesthetics on the inflammatory response in patients after cardiac surgery. The measurements of cytokines in the serum of patients undergoing cardiac pulmonary bypass grafting (CABG) showed a solid inflammatory response which was more pronounced, when using the noble gas xenon as anesthetic in comparison to sevoflurane. To assess the role of MIF on the migratory potential of peripheral blood mononuclear cells (PBMC) during I/R in CABG patients, chemotaxis analysis was performed, using serum samples taken at peri-operative time points and PBMCs of healthy volunteers. An increased migration towards post-operatively taken serum samples could be observed, which seemed to be more pronounced in serum samples of patients, who were anesthetized by sevoflurane. Compared to a blocking of MIF, the blocking of MIF-2 (MIF homologue) was able to decrease the migration of PBMCs towards serum samples significantly, indicating a more pronounced impact of MIF-2 on PBMCs as immune cells. In addition to these findings, only MIF-2 led to a significant increased migration of pro-inflammatory M1 macrophages, but not anti-inflammatory M2 macrophages, when compared to MIF. Neutrophils showed the strongest migration towards serum samples taken prior to surgery, and an again increased migration towards serum samples taken 24 h following surgery. A blocking of CXCL8, or CCL3 in the serum did not decrease neutrophil migration significantly. In addition, the influence of MIF serum levels on the mobilization of EPCs was investigated. Comparable to the peri-operative increase in MIF serum levels, also in vivo mobilization of early EPCs showed an increase. In vitro experiments showed an increased migration towards serum samples taken immediately after induction of reperfusion. A blocking of MIF in the same serum samples led to a significant decrease of EPC migration, indicating a strong influence of MIF on EPC mobilization. Of the measured cytokines, only MIF was able to mediate EPC migration in vitro at concentrations that were measured in serum samples. When comparing the extend of organ injury by the sequential organ failure assessment (SOFA) score, it was revealed that higher concentrations of circulating early EPCs were predictive for lower organ injuries after surgery. This study highlights especially a predominant role of MIF on the recruitment of EPCs in patients undergoing cardiac surgery.