David Simons

Hypoxia-induced endothelial secretion of macrophage migration inhibitory factor and role in endothelial progenitor cell recruitment

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine that was recently identified as a non‐cognate ligand of the CXC‐family chemokine receptors 2 and 4 (CXCR2 and CXCR4). MIF is expressed and secreted from endothelial cells (ECs) following atherogenic stimulation, exhibits chemokine‐like properties and promotes the recruitment of leucocytes to atherogenic endothelium. CXCR4 expressed on endothelial progenitor cells (EPCs) and EC‐derived CXCL12, the cognate ligand of CXCR4, have been demonstrated to be critical when EPCs are recruited to ischemic tissues. Here we studied whether hypoxic stimulation triggers MIF secretion from ECs and whether the MIF/CXCR4 axis contributes to EPC recruitment. Exposure of human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAoECs) to 1% hypoxia led to the specific release of substantial amounts of MIF. Hypoxia‐induced MIF release followed a biphasic behaviour. MIF secretion in the first phase peaked at 60 min. and was inhibited by glyburide, indicating that this MIF pool was secreted by a non‐classical mechanism and originated from pre‐formed MIF stores. Early hypoxia‐triggered MIF secretion was not inhibited by cycloheximide and echinomycin, inhibitors of general and hypoxia‐inducible factor (HIF)‐1α‐induced protein synthesis, respectively. A second phase of MIF secretion peaked around 8 hrs and was likely due to HIF‐1α‐induced de novo synthesis of MIF. To functionally investigate the role of hypoxia‐inducible secreted MIF on the recruitment of EPCs, we subjected human AcLDL+ KDR+ CD31+ EPCs to a chemotactic MIF gradient. MIF potently promoted EPC chemotaxis in a dose‐dependent bell‐shaped manner (peak: 10 ng/ml MIF). Importantly, EPC migration was induced by supernatants of hypoxia‐conditioned HUVECs, an effect that was completely abrogated by anti‐MIF‐ or anti‐CXCR4‐antibodies. Thus, hypoxia‐induced MIF secretion from ECs might play an important role in the recruitment and migration of EPCs to hypoxic tissues such as after ischemia‐induced myocardial damage.

Differential roles of angiogenic chemokines in endothelial progenitor cell-induced angiogenesis

This study aimed to analyze the role of endothelial progenitor cell (EPC)-derived angiogenic factors and chemokines in the multistep process driving angiogenesis with a focus on the recently discovered macrophage migration inhibitory factor (MIF)/chemokine receptor axis. Primary murine and murine embryonic EPCs (eEPCs) were analyzed for the expression of angiogenic/chemokines and components of the MIF/CXC chemokine receptor axis, focusing on the influence of hypoxic versus normoxic stimulation. Hypoxia induced an upregulation of CXCR2 and CXCR4 but not CD74 on EPCs and triggered the secretion of CXCL12, CXCL1, MIF, and vascular endothelial growth factor (VEGF). These factors stimulated the transmigration activity and adhesive capacity of EPCs, with MIF and VEGF exhibiting the strongest effects under hypoxia. MIF-, VEGF-, CXCL12-, and CXCL1-stimulated EPCs enhanced tube formation, with MIF and VEGF exhibiting again the strongest effect following hypoxia. Tube formation following in vivo implantation utilizing angiogenic factor-loaded Matrigel plugs was only promoted by VEGF. Coloading of plugs with eEPCs led to enhanced tube formation only by CXCL12, whereas MIF was the only factor which induced differentiation towards an endothelial and smooth muscle cell (SMC) phenotype, indicating an angiogenic and differentiation capacity in vivo. Surprisingly, CXCL12, a chemoattractant for smooth muscle progenitor cells, inhibited SMC differentiation. We have identified a role for EPC-derived proangiogenic MIF, VEGF and MIF receptors in EPC recruitment following hypoxia, EPC differentiation and subsequent tube and vessel formation, whereas CXCL12, a mediator of early EPC recruitment, does not contribute to the remodeling process. By discerning the contributions of key angiogenic chemokines and EPCs, these findings offer valuable mechanistic insight into mouse models of angiogenesis and help to define the intricate interplay between EPC-derived angiogenic cargo factors, EPCs, and the angiogenic target tissue.

Recent developments of dual-energy CT in oncology

Dual-energy computed tomography (DECT) can amply contribute to support oncological imaging: the DECT technique offers promising clinical applications in oncological imaging for tumour detection and characterisation while concurrently reducing the radiation dose. Fast image acquisition at two different X-ray energies enables the determination of tissue- or material-specific features, the calculation of virtual unenhanced images and the quantification of contrast medium uptake; thus, tissue can be characterised and subsequently monitored for any changes during treatment. DECT is already widely used, but its potential in the context of oncological imaging has not been fully exploited yet. The technology is the subject of ongoing innovation and increasingly with respect to its clinical potential, particularly in oncology. This review highlights recent state-of-the-art DECT techniques with a strong emphasis on ongoing DECT developments relevant to oncologic imaging, and then focuses on clinical DECT applications, especially its prospective uses in areas of oncological imaging.Key Points• Dual-energy CT (DECT) offers fast, robust, quantitative and functional whole-body imaging.• DECT provides improved tumour detection and more detailed tissue differentiation and characterisation.• DECT affords therapy monitoring with complementary information and reduced radiation dose.• The use of DECT in oncology is of increasing clinical importance.• The potential of DECT in oncology has not been fully exploited yet.

Blood Levels of Macrophage Migration Inhibitory Factor after Successful Resuscitation from Cardiac Arrest

Introduction Ischemia-reperfusion injury following cardiopulmonary resuscitation (CPR) is associated with a systemic inflammatory response, resulting in post-resuscitation disease. In the present study we investigated the response of the pleiotropic inflammatory cytokine macrophage migration inhibitory factor (MIF) to CPR in patients admitted to the hospital after out-of-hospital cardiac arrest (OHCA). To describe the magnitude of MIF release, we compared the blood levels from CPR patients with those obtained in healthy volunteers and with an aged- and gender-matched group of patients undergoing cardiac surgery with the use of extracorporeal circulation. Methods Blood samples of 17 patients with return of spontaneous circulation (ROSC) after OHCA were obtained upon admission to the intensive care unit, and 6, 12, 24, 72 and 96 h later. Arrest and treatment related data were documented according to the Utstein style. Results In patients after ROSC, MIF levels at admission (475.2±157.8 ng/ml) were significantly higher than in healthy volunteers (12.5±16.9 ng/ml, p<0.007) and in patients after cardiac surgery (78.2±41.6 ng/ml, p<0.007). Six hours after admission, MIF levels were decreased by more than 50% (150.5±127.2 ng/ml, p<0.007), but were not further reduced in the subsequent time course and remained significantly higher than the values observed during the ICU stay of cardiac surgical patients. In this small group of patients, MIF levels could not discriminate between survivors and non-survivors and were not affected by treatment with mild therapeutic hypothermia. Conclusion MIF shows a rapid and pronounced increase following CPR, hence allowing a very early assessment of the inflammatory response. Further studies are warranted in larger patient groups to determine the prognostic significance of MIF. Trial Registration ClinicalTrials.gov NCT01412619

High Postoperative Blood Levels of Macrophage Migration Inhibitory Factor Are Associated with Less Organ Dysfunction in Patients after Cardiac Surgery

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that exerts protective effects during myocardial ischemia/reperfusion injury. We hypothesized that elevated MIF levels in the early postoperative time course might be inversely associated with postoperative organ dysfunction as assessed by the simplified acute physiology score (SAPS) II and sequential organ failure assessment (SOFA) score in patients after cardiac surgery. A total of 52 cardiac surgical patients (mean age [± SD] 67 ± 10 years; EuroScore: 7 [2–11]) were enrolled in this monocenter, prospective observational study. Serum levels of MIF and clinical data were obtained after induction of anesthesia, at admission to the intensive care unit (ICU), 4 h after admission and at the first and second postoperative day. To characterize the magnitude of MIF release, we compared blood levels of samples from cardiac surgical patients with those obtained from healthy volunteers. We assessed patient outcomes using the SAPS II at postoperative d 1 and SOFA score for the first 3 d of the eventual ICU stay. Compared to healthy volunteers, patients had already exhibited elevated MIF levels prior to surgery (64 ± 50 versus 13 ± 17 ng/mL; p < 0.05). At admission to the ICU, MIF levels reached peak values (107 ± 95 ng/mL; p < 0.01 versus baseline) that decreased throughout the observation period and had already reached preoperative values 4 h later. Postoperative MIF values were inversely correlated with SAPS II and SOFA scores during the early postoperative stay. Moreover, MIF values on postoperative d 1 were related to the calculated cardiac power index (r = 0.420, p < 0.05). Elevated postoperative MIF levels are inversely correlated with organ dysfunction in patients after cardiac surgery.

Macrophage migration inhibitory factor is a potential inducer of endothelial progenitor cell mobilization after flap operation

BACKGROUND Endothelial progenitor cells (EPCs) promote angiogenesis and play an important role in tissue revascularization and wound healing. Yet, the exact stimuli and mechanisms for the mobilization remain understood poorly. Macrophage migration inhibitory factor (MIF), which is a structurally unique pleiotropic cytokine, has been suggested to play a role in EPC recruitment and thus was a target of this study. METHODS This study included 20 patients who underwent flap operation. Subjects were divided into 3 groups according to the pattern of flap applied. The number of circulating EPCs and serum levels of MIF or CXCL12 were determined at different time intervals. In vitro chemotaxis experiments using Transwell devices were carried out to test whether MIF promotes the chemotactic migration of EPCs. To underscore functionally the chemotactic potential of MIF toward EPCs in flap patients, the chemotactic effects of serum samples from all groups were also examined in the presence and absence of monoclonal anti-macrophage migration inhibitory factor and anti-CXCL12 antibodies on EPC recruitment using in vitro migration chambers. RESULTS In flap patients, the number of circulating EPCs and serum levels of MIF but not CXCL12 serum levels were increased markedly compared with preoperative levels at day 1 after operation, especially in the group of free microvascular flaps. Serum levels of CXCL12 in the flap patients were increased only significantly compared with the healthy control group. An analysis between EPCs and MIF revealed a significant correlation, whereas no correlation was observed for CXCL12. MIF exerted a dose-dependent, prochemotactic effect on isolated human EPCs, and serum samples from all flap patients promoted EPC migration. Importantly, this effect was blocked partially by anti-macrophage migration inhibitory factor and to a weaker extent by anti-CXCL12 antibodies. CONCLUSION We conclude that MIF plays an important role in the mobilization of EPCs, which is dependent on the degree of ischemia. Enhancement by MIF of chemotactic EPCs migration in vitro underpins its proposed in vivo function.

Glasgow Coma Scale and laboratory markers are superior to COHb in predicting CO intoxication severity.

Carbon monoxide (CO) intoxications can affect several organ systems and lead to coma or death in severe cases. To date, COHb is routinely used as a marker for detecting CO intoxication. In this retrospective study, we investigated 173 patients admitted with CO intoxication to our intensive care unit (ICU) over a period of 8 years. Standardised blood tests, chest X-ray and neurological status evaluation were performed on admission and throughout the inpatient treatment. The duration of inpatient treatment was considered to be an indication of the severity of CO-related illness. Interestingly, the data did not reveal a significant correlation between initial COHb level and the duration of inpatient treatment. Instead, a significant inverse correlation was found between the initial Glasgow Coma Scale and the duration of inpatient treatment. Furthermore, significant correlations were found between the duration of inpatient treatment and the occurrence of elevated leucocyte numbers, elevated C-reactive protein (CRP) serum concentrations and the presence of lung infiltrates. In conclusion, we postulate that clinical parameters, such as the Glasgow Coma Scale and the laboratory markers CRP and leucocyte count are adequate supportive tools for evaluating the severity of CO-related illness, and further, that the measurement of COHb alone is insufficient for this purpose.

Macrophage migration inhibitory factor—A potential diagnostic tool in severe burn injuries?

Serum macrophage migration inhibitory factor (MIF) and procalcitonin (PCT) concentrations as well as leucocyte numbers were evaluated in a retrospective study with 23 patients with severe burn injuries. The MIF and PCT concentrations as well as the number of leucocytes (LEU) were monitored over a period of 5 days. The total body surface area (TBSA) and sepsis-related organ failure assessment (SOFA) scores were also evaluated. The MIF, PCT concentrations and leucocyte counts were profoundly increased in all patients with severe burn wounds. At the time of admission into the intensive care unit, no significant differences were observed for the MIF and PCT levels between patients with a TBSA<60% (Group 1) and patients with a TBSA>60% (Group 2). After 48 h, however, the MIF and PCT levels reached very high levels in a subgroup of the patients, whereas these levels became normal again in other subgroups. The group of patients with a TBSA>60% was, therefore, subdivided in three groups (subgroups 2a-c). The MIF and PCT data pairs in these subgroups appeared to correlate in an inhomogeneous manner. These levels in the subgroup 2a (i.e., lethal within 5 days) were strongly elevated over those observed in Group 1 (TBSA<60%) and highly increased concentrations of both MIF and PCT correlated with lethal outcome. The combined determination of MIF and PCT might, therefore, be useful to discriminate between post-burn inflammation and systemic inflammatory response syndrome (SIRS) or sepsis with lethal outcome.

Calciphylaxis – a challenging & solvable task for plastic surgery? A case report

BackgroundCalciphylaxis (calcific uremic arteriolopathy) is rare and its pathogenesis is not fully understood. Indeed, Calciphylaxis presents a challenge through the course of its management which involve different specialities but unfortunately this disease so far has a poor prognosis. We herein present, in this case report, a multidisciplinary approach involving plastic surgeons with special regards to reconstructive approach after debridement procedures.Case presentationWe present a 21 years old male with a BMI of 38,2, who was transferred to our department from another hospital. Calciphylaxis has been diagnosed after receiving anticoagulation with phenprocoumon after a single event of pulmonary embolism. The INR on admission was 1,79. He had necrotic spots on both sides of the abdominal wall and on both thighs medially. During this time he underwent several reconstructive procedures in our department.ConclusionIt can be suggested that this agonizing disease needs indeed a multidisciplinary approach involving Nephrologists, Dermatologists, Intensive Care Physicians and Plastic Surgeons, taking into consideration that surgical correction can achieve further improvement in a specialized centre. Notwithstanding, further cohort studies should be approached clinically to insight the light on this disease with special regard to the prognosis after this approach.

Carbon monoxide intoxication versus myocardial infarction: An easy diagnosis?

Gerrit Grieb , David Simons *, Andrzej Piatkowski , Ertunc Altiok , Ron J. Eppstein , Jurgen Bernhagen , Norbert Pallua a Department of Plastic Surgery and Hand Surgery – Burn Center, University Hospital, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany b Institute of Biochemistry and Molecular Cell Biology, University Hospital, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany Department of Internal Medicine I – Cardiology, University Hospital, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany b u r n s 3 7 ( 2 0 1 1 ) e 2 9 – e 3 1