EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice

Background We have previously shown that EphrinA1/EphA expression profile changes in response to myocardial infarction (MI), exogenous EphrinA1-Fc administration following MI positively influences wound healing, and that deletion of the EphA2 Receptor (EphA2-R) exacerbates injury and remodeling. To determine whether or not ephrinA1-Fc would be of therapeutic value in the hyperglycemic infarcted heart, it is critical to evaluate how ephrinA1/EphA signaling changes in the hyperglycemic myocardium in response to MI. Methods Streptozotocin (STZ)-induced hyperglycemia in wild type (WT) and EphA2-receptor mutant (EphA2-R-M) mice was initiated by an intraperitoneal injection of STZ (150 mg/kg) 10 days before surgery. MI was induced by permanent ligation of the left anterior descending coronary artery and analyses were performed at 4 days post-MI. ANOVAs with Student-Newman Keuls multiple comparison post-hoc analysis illustrated which groups were significantly different, with significance of at least p < 0.05. Results Both WT and EphA2-R-M mice responded adversely to STZ, but only hyperglycemic EphA2-R-M mice had lower ejection fraction (EF) and fractional shortening (FS). At 4 days post-MI, we observed greater post-MI mortality in EphA2-R-M mice compared with WT and this was greater still in the EphA2-R-M hyperglycemic mice. Although infarct size was greater in hyperglycemic WT mice vs normoglycemic mice, there was no difference between hyperglycemic EphA2-R-M mice and normoglycemic EphA2-R-M mice. The hypertrophic response that normally occurs in viable myocardium remote to the infarct was noticeably absent in epicardial cardiomyocytes and cardiac dysfunction worsened in hyperglycemic EphA2-R-M hearts post-MI. The characteristic interstitial fibrotic response in the compensating myocardium remote to the infarct also did not occur in hyperglycemic EphA2-R-M mouse hearts to the same extent as that observed in the hyperglycemic WT mouse hearts. Differences in neutrophil and pan-leukocyte infiltration and serum cytokines implicate EphA2-R in modulation of injury and the differences in ephrinA1 and EphA6-R expression in governing this are discussed. Conclusions We conclude that EphA2-mutant mice are more prone to hyperglycemia-induced increased injury, decreased survival, and worsened LV remodeling due to impaired wound healing

B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction.

Acute myocardial infarction is a severe ischemic disease responsible for heart failure and sudden death. Here, we show that after acute myocardial infarction in mice, mature B lymphocytes selectively produce Ccl7 and induce Ly6C(hi) monocyte mobilization and recruitment to the heart, leading to enhanced tissue injury and deterioration of myocardial function. Genetic (Baff receptor deficiency) or antibody-mediated (CD20- or Baff-specific antibody) depletion of mature B lymphocytes impeded Ccl7 production and monocyte mobilization, limited myocardial injury and improved heart function. These effects were recapitulated in mice with B cell-selective Ccl7 deficiency. We also show that high circulating concentrations of CCL7 and BAFF in patients with acute myocardial infarction predict increased risk of death or recurrent myocardial infarction. This work identifies a crucial interaction between mature B lymphocytes and monocytes after acute myocardial ischemia and identifies new therapeutic targets for acute myocardial infarction.This work was supported by Inserm, British Heart Foundation (Z.M.), European Research Council (Z.M.), Fondation Coeur et Recherche (Z.M., T.S., N.D.), Fondation pour la Recherche Medicale (J.S.S.), European Union Seven Framework programme TOLERAGE (Z.M.), Fondation Leducq transatlantic network (C.J.B., D.T., A.T., J.S.S., Z.M.), National Institutes of Health grants AI56363 and AI057157, and a grant from The Lymphoma Research Foundation (T.F.T).This is the author accepted manuscript. The final version is available from Nature Publishing Group at http://dx.doi.org/10.1038/nm.3284

Autologous non-cultivated keratinocytesuspension in burn surgery - indications and techniques

The use of non-cultivated epithelial cells, processed from skin grafts, has been introduced in 1998. The ReCell©-kit offers a single use bedside kit for application of this technique and production of the cells intraoperatively. A major advantage of non cultivated autologous skin cells is the simplicity of their medical application. Accompanied by the presentation of eight patients that were treated with the ReCell© kit we present a concept for treatment of thermal and chemical burns, based on Versajet Exact© debridement and followed by applycation of non-cultivated autologous keratinocytes and fixation of cell with Biobrane© or Suprathel©.After debridement with Versajet Exact© at level 3 to 5 and proceesing of a skin graft with the ReCell© kit to produce a solution of non-cultivated epithelial cells, Biobrane© was fixated at the border of the burned skin area and tightened over the debrided skin. Now the non-cultivated epithelial cell solution was applied via a syringe below the Biobrane© and not sprayed like in the original protocol. Alternatively Suprathel© was soaked with the non-cultivated epithelial cell solution and applied on the wound bed. Follow up of the patients revealed an average scar quality of 3.1 (1 to 6) points according to Vancouver Scar Scale.We advocate to use the ReCell© kit in deep partial thickness chemical or thermal burns of small but aesthetically important regions of the body like face and neck. The presented technique of Biobrane© application minimizes the cell loss after spray application due to gravity with an accumulation of the cell solution in dorsal parts of the wound. After reepithelisation is completed the Biobrane© sheet can be removed easily with a reduced risk of injury of the regenerated skin.Die Nutzung von autologen nicht kultivierten, epithelialen Zellsuspensionen, welche aus Spalthaut gewonnen werden, wurde 1998 erstmalig vorgestellt. Mit dem ReCell©-Kit steht die Technologie zur autologen Hautzelltransplantation als Einmalverbrauchsmaterial zur Verfügung um die Zellsuspension intraoperativ herzustellen. Ein entscheidender Vorteil der Anwendung autologer nichtkultivierter Hautzellsuspension in der Verbrennungschirurgie ist die einfache Applikation. Anhand von acht Patientenbeispielen möchten wir nun ein Therapiekonzept vorstellen, welches auf einem Debridement mit dem Versajet Exact©, einer Defektdeckung mit autologer nichtkultivierter Keratinozytensuspension und deren Fixierung mit Biobrane© oder Suprathel© beruht.Nach Debridement der tief 2°-Verbrennungsareale mit dem Versajet Exact© auf Stufe 3 bis 5 und Aufbereitung der autologen nichtkultivierten Keratinozytensuspension mit dem ReCell Kit© wird Biobrane© an die Ränder des zu transplantierenden Areals fixiert, dieses wird über das Zielareal gespannt und die autologe nichtkultivierte Keratinozytensuspension wird über eine Kanüle unter das Biobrane© eingebracht. Alternativ kann auch Suprathel© mit der autologen nichtkultivierten Keratinozytensuspension getränkt und danach appliziert werden. Die Verlaufskontrollen ergaben eine durchschnittliche Narbenqualität von 3,1 ( 1 bis 6) Punkte nach Vancouver Scar Scale.Derzeit sehen wir die Indikation für eine nicht kultivierte Keratinozytensuspension bei 2b°-Verbrennungen kleinerer Hautareale ästhetisch wichtiger Regionen wie zum Beispiel dem Gesicht und Hals nach ausreichendem Debridement. Durch die beschriebene Technik lässt sich die Keratinozytensuspension nach exaktem Debridement einfach applizieren. Das typischerweise auftretende Verlaufen der aufgesprühten Suspension in Richtung der Schwerkraft und deren Ansammeln in tiefer gelegenen Arealen der Wunden kann durch das vorherige Aufbringen von Biobrane© vermieden werden. Nach erfolgter Reepithelisierung kann das Biobrane© einfach entfernt werden und die Gefahr eines Verletzens der Zellschicht kann somit deutlich reduziert werden