[Show abstract][Hide abstract] ABSTRACT: Background: The lack of early biomarkers for acute kidney injury (AKI) seriously inhibits the initiation of preventive and therapeutic measures for this syndrome in a timely manner. We tested the hypothesis that insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, function as early biomarkers for AKI after congenital heart surgery with cardiopulmonary bypass (CPB). Methods: We prospectively studied 51 children undergoing cardiac surgery with CPB. Serial urine samples were analyzed for [TIMP-2]N[IGFBP7]. The primary outcome measure was AKI defined by the pRIFLE criteria within 72 hours after surgery. Results: 12 children (24%) developed AKI within 1.67 (SE 0.3) days after surgery. Children who developed AKI after cardiac surgery had a significant higher urinary [TIMP-2]N[IGFBP7] as early as 4 h after the procedure, compared to children who did not develop AKI (mean of 1.93 ((ng/ml) 2 /1000) (SE 0.4) vs 0.47 ((ng/ml) 2 /1000) (SE 0.1), respectively; p,0.05). Urinary [TIMP-2]N[IGFBP7] 4 hours following surgery demonstrated an area under the receiver-operating characteristic curve of 0.85. Sensitivity was 0.83, and specificity was 0.77 for a cutoff value of 0.70 ((ng/ml) 2 /1000). Conclusions: Urinary [TIMP-2]N[IGFBP7] represent sensitive, specific, and highly predictive early biomarkers for AKI after surgery for congenital heart disease. Copyright: ß 2014 Meersch et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper. Funding: This study was supported by the German Research Foundation (ZA428/6-1 to A.Z.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PLoS ONE 10/2014; 9(10):e110865. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: During systemic inflammation, leucocytes are activated and extravasate into damaged tissue. Activation and recruitment are influenced by different mechanisms, including the interaction of leucocytes with platelets and neutrophil extracellular traps (NET) formation. Here, we investigated the molecular mechanism by which hydroxyethyl starch (HES 130/0.4) dampens systemic inflammation in vivo.
BJA British Journal of Anaesthesia 10/2014; · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute kidney injury (AKI) is a common complication in critically ill patients and is associated with increased morbidity and mortality. Sepsis is the most common cause of AKI. Considerable evidence now suggests that the pathogenic mechanisms of sepsis-induced AKI are different from those seen in other causes of AKI. This review focuses on the recent advances in this area and discusses possible therapeutic interventions that might derive from these new insights into the pathogenesis of sepsis-induced AKI.
[Show abstract][Hide abstract] ABSTRACT: The paradigm of platelets as mere mediators of hemostasis has long since been replaced by a dual role, hemostasis and inflammation. Now recognized as key players in innate and adaptive immune responses, platelets have the capacity to interact with virtually all known immune cells. These platelet-immune cell interactions are a hallmark of immunity as they can potently enhance immune cell functions and in some cases even constitute a prerequisite for host defense mechanisms like NETosis. In addition, recent studies have revealed a new role for platelets in immunity: They are ubiquitous sentinels and rapid first line immune responders as platelet-pathogen interactions within the vasculature appear to precede all other host defense mechanisms. Here, we discuss recent advances in our understanding of platelets as inflammatory cells and provide an exemplary review of their role to acute inflammation in acute lung injury.This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 09/2014; · 6.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The focus of this study is the characterization of human T cell blood-brain barrier migration and corresponding molecular trafficking signatures. We examined peripheral blood and cerebrospinal fluid immune cells from patients under long-term anti-very late antigen-4 (VLA-4)/natalizumab therapy (LTNT) and from CNS specimens. LTNT patients' cerebrospinal fluid T cells exhibited healthy central-/effector-memory ratios, but lacked CD49d and showed enhanced myeloma cell adhesion molecule (MCAM) expression. LTNT led to an increase of PSGL-1 expression on peripheral T cells. Although vascular cell adhesion molecule-1 (VLA-4 receptor) was expressed at all CNS barriers, P-selectin (PSGL-1-receptor) was mainly detected at the choroid plexus. Accordingly, in vitro experiments under physiological flow conditions using primary human endothelial cells and LTNT patients' T cells showed increased PSGL-1-mediated rolling and residual adhesion, even under VLA-4 blockade. Adhesion of MCAM(+)/TH17 cells was not affected by VLA-4 blocking alone, but was abrogated when both VLA-4 and MCAM were inhibited. Consistent with these data, MCAM(+) cells were detected in white matter lesions, and in gray matter of multiple sclerosis patients. Our data indicate that lymphocyte trafficking into the CNS under VLA-4 blockade can occur by using the alternative adhesion molecules, PSGL-1 and MCAM, the latter representing an exclusive pathway for TH17 cells to migrate over the blood-brain barrier.
The Journal of Experimental Medicine. 08/2014; 211(9):1833-1846.
[Show abstract][Hide abstract] ABSTRACT: The incidence of acute kidney injury (AKI) in critically ill patients is very high and is associated with an increased morbidity and mortality. In 2012 the Kidney Disease: Improving Global Outcome (KDIGO) guidelines were published in which evidence-based practical recommendations are given for the evaluation and management of patients with AKI. The first section of the KDIGO guidelines deals with the unification of earlier consensus definitions and staging criteria for AKI. The subsequent sections of the guidelines cover the prevention and treatment of AKI as well as the management of renal replacement therapy (RRT) in patients with AKI. In each section the existing evidence is discussed and a specific treatment recommendation is given. The guidelines appreciates that there is insufficient evidence for many of the recommendations. As a specific pharmacological therapy is missing, an early diagnosis, aggressive hemodynamic optimization, tight volume control, and avoidance of nephrotoxic drugs are the only interventions to prevent AKI. If renal replacement therapy is required different modalities are available to provide an effective therapy with a low rate of adverse effects.
[Show abstract][Hide abstract] ABSTRACT: This review summarizes the approach to and recent developments in the treatment of acute right ventricular dysfunction and failure in the perioperative setting. Right ventricular failure, defined as the inability to deliver sufficient blood flow through the pulmonary circulation at normal central venous pressure, is a common problem in the perioperative setting and is associated with an increased mortality. The failure of the right ventricle is caused by reduced right ventricular contractility or an increased right ventricular afterload or both.
[Show abstract][Hide abstract] ABSTRACT: Acute inflammation is the pathophysiological basis of important clinical conditions associated with organ failure. The initial inflammatory response is controlled by the chemokine system, yet recent data have indicated that the neuronal guidance cues are significantly involved in the orchestration of this process. Previous work has shown the pro-inflammatory capacity of the guidance cue semaphorin 7a (Sema 7a), but the role of one of its target receptors, the plexin C1 (PLXNC1) receptor is to date unknown. We report here that PLXNC1 is expressed outside the nervous system and induced during acute inflammation. PLXNC1−/− mice with C57BL/6 background demonstrated decreased inflammatory responses during zymosan A (ZyA)-induced peritonitis. Subsequent in vivo studies revealed altered rolling, adhesion and transmigration properties of PLXNC1−/− leukocytes. Blockade of PLXNC1 was associated with attenuated chemotactic transendothelial migration properties in vitro. Studies in chimeric mice revealed that hematopoietic PLXNC1−/− animals demonstrated an attenuated inflammatory response. To probe the therapeutic potential of PLXNC1 we treated C57BL/6 WT mice with an anti-PLXNC1 antibody and a PLXNC1 binding peptide. Both of these interventions significantly dampened ZyA-induced peritonitis. These results implicate an important role of PLXNC1 during an acute inflammatory response and indicate PLXNC1 as a potential target for the control of conditions associated with acute inflammation.This article is protected by copyright. All rights reserved
European Journal of Immunology 05/2014; · 4.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tyrosine phosphorylation of the adhesion molecule VE-cadherin is assumed to affect endothelial junction integrity. However, it remains unclear whether tyrosine residues of VE-cadherin are required for the induction of vascular permeability and the regulation of leukocyte extravasation in vivo. We found here that knock-in mice expressing a Y685F mutant of VE-cadherin had impaired induction of vascular permeability, but those expressing a Y731F mutant did not. In contrast, mice expressing the Y731F VE-cadherin mutant showed decreased neutrophil-extravasation in cremaster tissue, but those expressing the Y685F mutant did not. Whereas inflammatory mediators induced the phosphorylation of Tyr685 in vivo, Tyr731 showed high baseline phosphorylation. Leukocytes triggered dephosphorylation of Tyr731 via the tyrosine phosphatase SHP-2, which allowed the adaptin AP-2 to bind and initiate endocytosis of VE-cadherin. Thus, Tyr685 and Tyr731 of VE-cadherin distinctly and selectively regulate the induction of vascular permeability or leukocyte extravasation.
[Show abstract][Hide abstract] ABSTRACT: Difficulties in prediction and early identification of (acute kidney injury) AKI have hindered the ability to develop preventive and therapeutic measures for this syndrome. We tested the hypothesis that a urine test measuring insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in acute kidney injury (AKI), could predict AKI in cardiac surgery patients.
We studied 50 patients at high risk for AKI undergoing cardiac surgery with cardiopulmonary bypass (CPB). Serial urine samples were analyzed for [TIMP-2]*[IGFBP7] concentrations. The primary outcome measure was AKI as defined by international consensus criteria following surgery. Furthermore, we investigated whether urine [TIMP-2]*[IGFBP7] could predict renal recovery from AKI prior to hospital discharge.
26 patients (52%) developed AKI. Diagnosis based on serum creatinine and/or oliguria did not occur until 1-3 days after CPB. In contrast, urine concentration of [TIMP-2]*[IGFBP7] rose from a mean of 0.49 (SE 0.24) at baseline to 1.51 (SE 0.57) 4 h after CPB in patients who developed AKI. The maximum urinary [TIMP-2]*[IGFBP7] concentration achieved in the first 24 hours following surgery (composite time point) demonstrated an area under the receiver-operating characteristic curve of 0.84. Sensitivity was 0.92, and specificity was 0.81 for a cutoff value of 0.50. The decline in urinary [TIMP-2]*[IGFBP7] values was the strongest predictor for renal recovery.
Urinary [TIMP-2]*[IGFBP7] serves as a sensitive and specific biomarker to predict AKI early after cardiac surgery and to predict renal recovery.
www.germanctr.de/, DRKS-ID: DRKS00005062.
PLoS ONE 01/2014; 9(3):e93460. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To enable leukocyte adhesion to activated endothelium, the leukocyte receptor P-selectin is released from Weibel-Palade bodies (WPB) to the endothelial cell surface where it is stabilized by CD63. Here we report that loss of annexin A8 (anxA8) in human umbilical vein endothelial cells (HUVEC) strongly decreases cell surface presentation of CD63 and P-selectin, with a concomitant reduction in leukocyte rolling and adhesion. We confirm the compromised leukocyte adhesiveness in inflammatory-activated endothelial venules of anxA8-deficient mice. We find that WPB of anxA8-deficient HUVEC contain less CD63, and that this is caused by improper transport of CD63 from late multivesicular endosomes to WPB, with CD63 being retained in intraluminal vesicles. Consequently, reduced CD63 cell surface levels are seen following WPB exocytosis, resulting in enhanced P-selectin re-internalization. Our data support a model in which anxA8 affects leukocyte recruitment to activated endothelial cells by supplying WPB with sufficient amounts of the P-selectin regulator CD63.
[Show abstract][Hide abstract] ABSTRACT: There is emerging evidence that neutrophil extracellular traps (NETs) play important roles in inflammatory processes. Here, we report that neutrophils have to be simultaneously activated by integrin-mediated outside-in- and G-protein coupled receptor (GPCR) signaling to induce NET formation in acute lung injury (ALI), which is associated with a high mortality in critically ill patients. NETs consist of decondensed chromatin decorated with granular and cytosolic proteins and they can trap extracellular pathogens. The prerequisite for NET formation is the activation of neutrophils and the release of their DNA. In a neutrophil- and platelet-dependent mouse model of ventilator-induced lung injury (VILI), NETs were found in the lung microvasculature and circulating NET components increased in the plasma. In this model, blocking integrin-mediated outside-in or either GPCR-signaling or heteromerization of platelet chemokines decreased NET formation and lung injury. Targeting NET components by using DNase1 or neutrophil elastase-deficient mice protected mice from ALI, whereas DNase1-deficient mice had an aggravated ALI, suggesting that NETs directly influence the severity of ALI. These data suggest that NETs form in the lungs during VILI, contribute to the disease process, and thus may be a promising new direction for the treatment of ALI.
[Show abstract][Hide abstract] ABSTRACT: The inappropriate activation, positioning, and recruitment of leukocytes are implicated in the pathogenesis of multiple organ failure in sepsis. Although the local anesthetic lidocaine modulates inflammatory processes, the effects of lidocaine in sepsis are still unknown. This double-blinded, prospective, randomized clinical trial was conducted to investigate the effect of lidocaine on leukocyte recruitment in septic patients. Fourteen septic patients were randomized to receive either a placebo (n = 7) or a lidocaine (n = 7) bolus (1.5 mg/kg), followed by continuous infusion (100 mg/h for patients >70 kg or 70 mg/h for patients <70 kg) over a period of 48 h. Selectin-mediated slow rolling, chemokine-induced arrest, and transmigration were investigated by using flow chamber and transmigration assays. Lidocaine treatment abrogated chemokine-induced neutrophil arrest and significantly impaired neutrophil transmigration through endothelial cells by inhibition of the protein kinase C-θ while not affecting the selectin-mediated slow leukocyte rolling. The observed results were not attributable to changes in surface expression of adhesion molecules or selectin-mediated capturing capacity, indicating a direct effect of lidocaine on signal transduction in neutrophils. These data suggest that lidocaine selectively inhibits chemokine-induced arrest and transmigration of neutrophils by inhibition of protein kinase C-θ while not affecting selectin-mediated slow rolling. These findings may implicate a possible therapeutic role for lidocaine in decreasing the inappropriate activation, positioning, and recruitment of leukocytes during sepsis.
The Journal of Immunology 11/2013; · 5.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The CXC chemokine receptor type 4 (CXCR4), which is a G-protein coupled receptor, and its ligand CXCL12 play an important role in neutrophil homeostasis and inflammation. This review focuses on involvement of the CXCL12/CXCR4 axis in inflammation and different inflammatory diseases and depicts that blocking CXCR4 is an attractive therapeutic strategy.
Binding of CXCL12 to CXCR4 retains immature neutrophils in the bone marrow and also participates in leukocyte recruitment into inflamed tissue. The CXCL12/CXCR4 axis is also involved in several inflammatory processes and diseases including the WHIM (warts, hypogammaglobulinemia, infections and myelokathexis) syndrome, HIV, autoimmune disorders, ischemic injury, and pulmonary fibrosis.
Based on these findings, blocking CXCR4 seems to be a therapeutic strategy in inflammatory diseases. Several promising CXCR4 antagonists are in different stages of development and clinical trials. Currently, only plerixafor (AMD3100) has been approved for short-term application.
Current opinion in hematology 11/2013; · 5.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neutrophils are recruited from the blood to sites of inflammation, where they contribute to immune defense but may also cause tissue damage. During inflammation, neutrophils roll along the microvascular endothelium before arresting and transmigrating. Arrest requires conformational activation of the integrin lymphocyte function-associated antigen 1 (LFA-1), which can be induced by selectin engagement. Here, we demonstrate that a subset of P-selectin glycoprotein ligand-1 (PSGL-1) molecules is constitutively associated with L-selectin. Although this association does not require the known lectin-like interaction between L-selectin and PSGL-1, the signaling output is dependent on this interaction and the cytoplasmic tail of L-selectin. The PSGL-1-L-selectin complex signals through Src family kinases, ITAM domain-containing adaptor proteins, and other kinases to ultimately result in LFA-1 activation. The PSGL-1-L-selectin complex-induced signaling effects on neutrophil slow rolling and recruitment in vivo demonstrate the functional importance of this pathway. We conclude that this is a signaling complex specialized for sensing adhesion under flow.
Journal of Experimental Medicine 10/2013; · 13.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Beyond its well-established roles in mediating leukocyte rolling, E-selectin is emerging as a multifunctional receptor capable of inducing integrin activation in neutrophils, and of regulating various biological processes in hematopoietic precursors. While these effects suggest important homeostatic contributions of this selectin in the immune and hematological systems, the ligands responsible for transducing these effects in different leukocyte lineages are not well defined. We have characterized mice deficient in ESL-1, or in both PSGL-1 and ESL-1, to explore and compare the contributions of these glycoproteins in immune and hematopoietic cell trafficking. In the steady-state, ESL-1 deficiency resulted in a moderate myeloid expansion that became more prominent when both glycoproteins were eliminated. During inflammation, PSGL-1 dominated E-selectin binding, rolling, integrin activation and extravasation of mature neutrophils, but only the combined deficiency in PSGL-1 and ESL-1 completely abrogated leukocyte recruitment. Surprisingly, we find that the levels of ESL-1 were strongly elevated in hematopoietic progenitor cells (HPC). These elevations correlated with a prominent function of ESL-1 for E-selectin binding and for migration of HPC into the bone marrow. Our results uncover dominant roles for ESL-1 in the immature compartment, and a functional shift towards PSGL-1-dependence in mature neutrophils.