Alexander Zarbock

Heinrich-Heine-Universität Düsseldorf, Düsseldorf, North Rhine-Westphalia, Germany

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Publications (128)925.89 Total impact

  • A. Zarbock · C. Schmidt · H. Van Aken

    No preview · Article · Feb 2016
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    ABSTRACT: Neutrophils are recruited from the blood to sites of sterile inflammation, where they are involved in wound healing but can also cause tissue damage. During sterile inflammation, necrotic cells release pro-inflammatory molecules including formylated peptides. However, the signaling pathway triggered by formylated peptides to integrin activation and leukocyte recruitment is unknown. By using spinning-disk confocal intravital microscopy, we examined the molecular mechanisms of leukocyte recruitment to sites of focal hepatic necrosis in vivo. We demonstrated that the Bruton’s tyrosine kinase (Btk) was required for multiple Mac-1 activation events involved in neutrophil recruitment and functions during sterile inflammation triggered by fMLF. The Src family kinase Hck, Wiskott-Aldrich-syndrome protein, and phospholipase Cγ2 were also involved in this pathway required for fMLF-triggered Mac-1 activation and neutrophil recruitment. Thus, we have identified a neutrophil Btk signalosome that is involved in a signaling pathway triggered by formylated peptides leading to the selective activation of Mac-1 and neutrophil recruitment during sterile inflammation.
    No preview · Article · Jan 2016 · Immunity
  • Alexander Zarbock · Christoph Schmidt

    No preview · Article · Dec 2015 · Current opinion in anaesthesiology
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    ABSTRACT: In acute and chronic inflammation, neutrophils and platelets, both of which promote monocyte recruitment, are often activated simultaneously. We investigated how secretory products of neutrophils and platelets synergize to enhance the recruitment of monocytes. We found that neutrophil-borne human neutrophil peptide 1 (HNP1, α-defensin) and platelet-derived CCL5 form heteromers. These heteromers stimulate monocyte adhesion through CCR5 ligation. We further determined structural features of HNP1-CCL5 heteromers and designed a stable peptide that could disturb proinflammatory HNP1-CCL5 interactions. This peptide attenuated monocyte and macrophage recruitment in a mouse model of myocardial infarction. These results establish the in vivo relevance of heteromers formed between proteins released from neutrophils and platelets and show the potential of targeting heteromer formation to resolve acute or chronic inflammation.
    No preview · Article · Dec 2015 · Science translational medicine
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    ABSTRACT: Vascular endothelial (VE)-protein tyrosine phosphatase (PTP) associates with VE-cadherin, thereby supporting its adhesive activity and endothelial junction integrity. VE-PTP also associates with Tie-2, dampening the tyrosine kinase activity of this receptor that can support stabilization of endothelial junctions. Here, we have analyzed how interference with VE-PTP affects the stability of endothelial junctions in vivo. Blocking VE-PTP by antibodies, a specific pharmacological inhibitor (AKB-9778), and gene ablation counteracted vascular leak induction by inflammatory mediators. In addition, leukocyte transmigration through the endothelial barrier was attenuated. Interference with Tie-2 expression in vivo reversed junction-stabilizing effects of AKB-9778 into junction-destabilizing effects. Furthermore, lack of Tie-2 was sufficient to weaken the vessel barrier. Mechanistically, inhibition of VE-PTP stabilized endothelial junctions via Tie-2, which triggered activation of Rap1, which then caused the dissolution of radial stress fibers via Rac1 and suppression of nonmuscle myosin II. Remarkably, VE-cadherin gene ablation did not abolish the junction-stabilizing effect of the VE-PTP inhibitor. Collectively, we conclude that inhibition of VE-PTP stabilizes challenged endothelial junctions in vivo via Tie-2 by a VE-cadherin-independent mechanism. In the absence of Tie-2, however, VE-PTP inhibition destabilizes endothelial barrier integrity in agreement with the VE-cadherin-supportive effect of VE-PTP.
    No preview · Article · Dec 2015 · Journal of Experimental Medicine
  • Melanie Meersch · Christoph Schmidt · Alexander Zarbock

    No preview · Article · Nov 2015 · Current Opinion in Anaesthesiology
  • Alexander Zarbock · John A Kellum
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    ABSTRACT: Objective: Acute kidney injury is a common complication in critically ill patients and is associated with increased morbidity and mortality. Sepsis, major surgery, and nephrotoxic drugs are the most common causes of acute kidney injury. There is currently no effective strategy available to prevent or treat acute kidney injury. Therefore, novel treatment regimens are required to decrease acute kidney injury prevalence and to improve clinical outcomes. Remote ischemic preconditioning, triggered by brief episodes of ischemia and reperfusion applied in distant tissues or organs before the injury of the target organ, attempts to invoke adaptive responses that protect against acute kidney injury. We sought to evaluate the clinical evidence for remote ischemic preconditioning as a potential strategy to protect the kidney and to review the underlying mechanisms in light of recent studies. Data sources: We searched PubMed for studies reporting the effect of remote ischemic preconditioning on kidney function in surgical patients (search terms: "remote ischemic preconditioning," "kidney function," and "surgery"). We also reviewed bibliographies of relevant articles to identify additional citations. Study selection: Published studies, consisting of randomized controlled trials, are reviewed. Data extraction: The authors used consensus to summarize the evidence behind the use of remote ischemic preconditioning. Data synthesis: In addition, the authors suggest patient populations and clinical scenarios in which remote ischemic preconditioning might be best applied. Conclusions: Several experimental and clinical studies have shown tissue-protective effects of remote ischemic preconditioning in various target organs, including the kidneys. Remote ischemic preconditioning may offer a novel, noninvasive, and inexpensive treatment strategy for decreasing acute kidney injury prevalence in high-risk patients. Although many new studies have further advanced our knowledge in this area, the appropriate intensity of remote ischemic preconditioning, its mechanisms of action, and the role of biomarkers for patient selection and monitoring are still unknown.
    No preview · Article · Oct 2015 · Critical care medicine
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    ABSTRACT: Chemokines are required for leukocyte recruitment and appropriate host defense and act through G-protein coupled receptors (GPCR), which induce downstream-signaling leading to integrin activation. Although the alpha- and beta- subunits of the GPCRs are the first intracellular molecules that transduce signals following ligand binding and are therefore indispensable for downstream signaling, relatively little is known about their contribution to LFA-1 activation and leukocyte recruitment. We employed knock-out mice and used shRNA to knock-down GNB-isoforms (GNB1, GNB2, GNB4 and GNB5) in HL60 cells and primary murine hematopoietic cells. Neutrophil function was assessed using intravital microscopy, flow chamber assays, and chemotaxis and biochemistry studies. Unexpectedly, we discovered that all expressed GNB-isoforms are required for LFA-1 activation. Their down-regulation led to a significant impairment of LFA-1 activation, which was demonstrated in vitro and in vivo. Furthermore, we showed that GPCR-activation leads to Rac1-dependent activation of both, Plcβ2 and Plcβ3. They act non-redundantly to produce IP3, mediated intracellular Ca(2+)-flux, and LFA-1 activation that supported chemokine-induced arrest in vivo. In a complex inflammatory disease model, Plcβ2-, Plcβ3- or Rac1-deficient mice were protected from LPS-induced lung injury. Taken together, we demonstrate that all GNB-isoforms are required for chemokine-induced downstream signaling, and Rac1, Plcβ2 and Plcβ3 are critically involved in integrin activation and leukocyte arrest.
    No preview · Article · Oct 2015 · Blood
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    Preview · Article · Oct 2015
  • J Rossaint · A Zarbock
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    ABSTRACT: Acute kidney injury (AKI) is a common complication in hospitalized patients and great efforts by leading experts have been made in order to establish common definitions of AKI. The clinical use of these consensus definitions has led to a substantially improved understanding of AKI. In addition, the consensus definitions allow comparing the incidence of AKI and outcomes between different patient populations. As a result it became evident, that AKI in the western population represents a clinical syndrome with an incidence close to myocardial infarction. The aim of this review is to revisit the current concepts and definitions of AKI, to highlight the diagnosis, and to emphasize the epidemiological characteristics of AKI. Here, we will focus on the available literature reporting the epidemiology of AKI in critically ill patients. Sepsis, major surgery, and nephrotoxic drugs are the main causes of AKI in these patients and the occurrence of AKI is associated with an increased probability for sustained chronic kidney injury. We also discuss the concept of renal angina as a possible future concept for improved clinical risk stratification to discover AKI. In the context of this new concept, we emphasize the use of novel biomarkers in the diagnosis of AKI which may hold the potential to improve the early diagnosis and prevention of AKI in the clinical setting.
    No preview · Article · Sep 2015 · Minerva urologica e nefrologica = The Italian journal of urology and nephrology
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    ABSTRACT: Neutrophil recruitment to the site of inflammation plays a pivotal role in host defense. However, overwhelming activation and accumulation of neutrophils in the tissue may cause tissue damage and autoimmunity due to the release of cytokines, oxidants, and proteases. Neutrophil adhesion in acute inflammation is initiated by activation of αLβ2 (LFA-1), which can be induced by rolling on E-selectin (slowly) or by exposure to the chemokine CXCL1 (rapidly). Despite the clinical importance, cell-intrinsic molecular mechanisms of negative regulation of integrin adhesiveness and neutrophil recruitment are poorly understood. Mice deficient in the tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase 1 (Shp1) show increased leukocyte adhesion, but the interpretation of these data is limited by the severe global phenotype of these mice. In this study, we used mice with global and myeloid-restricted deletion of Shp1 to study neutrophil arrest, adhesion, crawling, and transendothelial migration in vitro and in vivo. Shp1 deficiency results in increased neutrophil adhesion in vivo; however, neutrophil crawling, transmigration, and chemotaxis were reduced in these mice. Mechanistically, Shp1 binds and controls PIPKIγ activity and, thereby, modulates phosphatidylinositol (4,5)-bisphosphate levels and adhesion. Thus, Shp1 is involved in the deactivation of integrins and regulation of neutrophil recruitment into inflamed tissue. Copyright © 2015 by The American Association of Immunologists, Inc.
    No preview · Article · Jun 2015 · The Journal of Immunology
  • Alexander Zarbock · Kindgen Milles
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    ABSTRACT: Acute kidney injury (AKI) is a common and serious complication that significantly increases morbidity, mortality, and cost of care after surgery. In this article, we review recent studies that deal with strategies for renal protection and the prevention of AKI after surgery. A prerequisite for any prophylactic intervention is the identification of patients at risk for AKI or those with acute kidney damage before kidney function deteriorates. In this context, new biomarkers can help to detect cellular injury early. This way, a window for interventions can be opened. Several studies demonstrated the tissue-protective effect of remote ischemic preconditioning in various organs. There is clear evidence that use of balanced crystalloid fluids and the avoidance of hyperchloremic solutions for infusion therapy can reduce the incidence of AKI. Preliminary data show a protective effect if dexmedetomidine is used as a sedative agent following cardiac surgery. The most important intervention with proven efficacy to protect from AKI is aggressive hemodynamic stabilization. Early identification of patients at risk for AKI is crucial to apply any protective intervention. An improved perioperative management is required to prevent AKI. Although pharmacological therapies aiming to protect AKI are under evaluation, hemodynamic optimization and avoidance of nephrotoxic drugs are critical for perioperative patient.
    No preview · Article · Jun 2015 · Current opinion in anaesthesiology
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    ABSTRACT: No interventions have yet been identified to reduce the risk of acute kidney injury in the setting of cardiac surgery. To determine whether remote ischemic preconditioning reduces the rate and severity of acute kidney injury in patients undergoing cardiac surgery. In this multicenter trial, we enrolled 240 patients at high risk for acute kidney injury, as identified by a Cleveland Clinic Foundation score of 6 or higher, between August 2013 and June 2014 at 4 hospitals in Germany. We randomized them to receive remote ischemic preconditioning or sham remote ischemic preconditioning (control). All patients completed follow-up 30 days after surgery and were analyzed according to the intention-to-treat principle. Patients received either remote ischemic preconditioning (3 cycles of 5-minute ischemia and 5-minute reperfusion in one upper arm after induction of anesthesia) or sham remote ischemic preconditioning (control), both via blood pressure cuff inflation. The primary end point was the rate of acute kidney injury defined by Kidney Disease: Improving Global Outcomes criteria within the first 72 hours after cardiac surgery. Secondary end points included use of renal replacement therapy, duration of intensive care unit stay, occurrence of myocardial infarction and stroke, in-hospital and 30-day mortality, and change in acute kidney injury biomarkers. Acute kidney injury was significantly reduced with remote ischemic preconditioning (45 of 120 patients [37.5%]) compared with control (63 of 120 patients [52.5%]; absolute risk reduction, 15%; 95% CI, 2.56%-27.44%; P = .02). Fewer patients receiving remote ischemic preconditioning received renal replacement therapy (7 [5.8%] vs 19 [15.8%]; absolute risk reduction, 10%; 95% CI, 2.25%-17.75%; P = .01), and remote ischemic preconditioning reduced intensive care unit stay (3 days [interquartile range, 2-5]) vs 4 days (interquartile range, 2-7) (P = .04). There was no significant effect of remote ischemic preconditioning on myocardial infarction, stroke, or mortality. Remote ischemic preconditioning significantly attenuated the release of urinary insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinases 2 after surgery (remote ischemic preconditioning, 0.36 vs control, 0.97 ng/mL2/1000; difference, 0.61; 95% CI, 0.27-0.86; P < .001). No adverse events were reported with remote ischemic preconditioning. Among high-risk patients undergoing cardiac surgery, remote ischemic preconditioning compared with no ischemic preconditioning significantly reduced the rate of acute kidney injury and use of renal replacement therapy. The observed reduction in the rate of acute kidney injury and the need for renal replacement warrants further investigation. German Clinical Trials Register Identifier: DRKS00005333.
    No preview · Article · May 2015 · JAMA The Journal of the American Medical Association

  • No preview · Article · May 2015 · Thrombosis and Haemostasis
  • J. Rossaint · H. Van Aken · A. Hidalgo · A. Zarbock

    No preview · Article · May 2015 · European Journal of Clinical Investigation
  • Florian Kraft · Christoph Schmidt · Hugo Van Aken · Alexander Zarbock
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    ABSTRACT: Patients undergoing cardiac surgery with extracorporeal circulation (EC) frequently develop a systemic inflammatory response syndrome. Surgical trauma, ischaemia-reperfusion injury, endotoxaemia and blood contact to nonendothelial circuit compounds promote the activation of coagulation pathways, complement factors and a cellular immune response. This review discusses the multiple pathways leading to endothelial cell activation, neutrophil recruitment and production of reactive oxygen species and nitric oxide. All these factors may induce cellular damage and subsequent organ injury. Multiple organ dysfunction after cardiac surgery with EC is associated with an increased morbidity and mortality. In addition to the pathogenesis of organ dysfunction after EC, this review deals with different therapeutic interventions aiming to alleviate the inflammatory response and consequently multiple organ dysfunction after cardiac surgery. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Mar 2015 · Baillière&#x27 s Best Practice and Research in Clinical Anaesthesiology
  • J. M. Herter · J. Rossaint · A. Zarbock

    No preview · Article · Mar 2015 · Journal of Thrombosis and Haemostasis
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    Full-text · Dataset · Feb 2015
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    Jan Rossaint · Alexander Zarbock
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    ABSTRACT: Platelets have a longstanding recognition as an essential cellular component of the coagulation system. However, substantial research over the last decade has added another important aspect to platelet function in that they are also an integral part of the innate immune system. Complex organisms are facing a constant threat of infections by invading pathogens, and they have developed a sophisticated and elegant measure to combat this threat, namely the immune system. Leukocyte recruitment to sites of infections is an essential step at the forefront of the immune response. Platelets have been shown to be involved in several steps of this process and they are an integrated connecting element among hemostasis, host defense, and additional immunological functions (e.g. neutrophil extracellular traps formation). However, the immune system also requires a tight regulation, as an overshooting immune response carries the risk of harming the host itself. This review aims at highlighting the unique features and molecular mechanisms that allow for the interactions of platelets and leukocytes and the regulation of this process. Furthermore, this article identifies the functional relevance of these events for the immune response. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email:
    Preview · Article · Feb 2015 · Cardiovascular Research
  • Alexander Zarbock · Hugo Van Aken · Christoph Schmidt
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    ABSTRACT: Although advancements in perioperative care have been made over the last decades, the perioperative outcome could not be improved adequately. Therefore, new therapeutic strategies are required to decrease morbidity and all-cause mortality in surgical patients. Remote ischemic preconditioning (RIPC), defined as brief and transient episodes of ischemia at a remote site before a subsequent injury of the target organ, is an adaptive response to protect for organ injury elicited by different stimuli. This review evaluates the current clinical evidence for RIPC as a potential tissue-protective strategy and discusses the underlying mechanism. Several studies demonstrated the tissue-protective effect of RIPC in various organs, including the heart, brain, and kidney. However, the existence of controversial results may be explained by the fact that different study protocols were used and different patient populations were recruited. RIPC may offer a novel inexpensive and noninvasive therapeutic strategy to alleviate organ injury in the perioperative period. However, adequately powered, large, multicenter clinical studies are necessary to accurately determine whether ischemic conditioning can improve the clinical outcomes of patients at risk for ischemia-reperfusion injury.
    No preview · Article · Jan 2015 · Current Opinion in Anaesthesiology

Publication Stats

4k Citations
925.89 Total Impact Points


  • 2015
    • Heinrich-Heine-Universität Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2014-2015
    • University of Pittsburgh
      • Department of Critical Care Medicine
      Pittsburgh, Pennsylvania, United States
  • 2011-2015
    • Max Planck Institute for Molecular Biomedicine
      Muenster, North Rhine-Westphalia, Germany
    • Universität Bremen
      • Center for Biomolecular Interactions CBIB
      Bremen, Bremen, Germany
  • 2006-2015
    • University of Münster
      • • Department of Anesthesiology, Intensive Care and Pain Therapy
      • • Department of Anaesthesiology and Intensive Care
      Muenster, North Rhine-Westphalia, Germany
  • 2005-2015
    • Universitätsklinikum Münster
      • • Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie
      • • Klinik und Poliklinik für Neurologie
      Muenster, North Rhine-Westphalia, Germany
  • 2013
    • Spanish National Centre for Cardiovascular Research
      • Department of Epidemiology, Atherothrombosis and Imaging (EAI)
      Madrid, Madrid, Spain
  • 2008-2012
    • La Jolla Institute for Allergy & Immunology
      La Jolla, California, United States
  • 2006-2007
    • University of Virginia
      • • Department of Biomedical Engineering
      • • Robert M. Berne Cardiovascular Research Center
      Charlottesville, Virginia, United States