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1.
Cardiovasc Res ; 101(3): 400-10, 2014 Mar 01.
Article in English | MEDLINE | ID: mdl-24323314

ABSTRACT

AIMS: Thrombomodulin (TM), via its lectin-like domain (LLD), exhibits anti-inflammatory properties partly by sequestering the pro-inflammatory cytokine, high-mobility group box 1 (HMGB1). Since myocardial damage after ischaemia and reperfusion is mediated by inflammation, we evaluated the cardioprotective effects of the LLD of TM. Using an in vivo mouse model of transient ischaemia and in vitro models of cardiomyocyte hypoxia, we assessed the ability of the LLD to suppress HMGB1-mediated activation of the receptors, receptor for advanced glycation endproducts (RAGEs) and Toll-like receptors (TLRs) 2 and 4. METHODS AND RESULTS: Thirty-minute myocardial ischaemia was induced in isoflurane-anaesthetized mice followed by 24 h of reperfusion in wild-type (WT) mice, in mice lacking the LLD of TM (TM(LeD/LeD) mice), and in WT with systemic overexpression of the LLD of TM induced by hydrodynamic transfection. Infarct size, HMGB1 protein, and apoptotic cells were significantly increased in TM(LeD/LeD) mice when compared with WT. Neonatal rat cardiomyocytes transfected with TLR2-, TLR4-, and RAGE-siRNA were exposed to hypoxia (0.8% O2) and reoxygenation (21% O2). HMGB1 augmented hypoxia-induced apoptosis in TLR2- but not in RAGE- or TLR4-suppressed cells. Administration of HMGB1- and TLR2-blocking antibodies in TM(LeD/LeD) mice prior to myocardial ischaemia diminished apoptosis. Therapeutic systemic gene therapy using the LLD reduced the infarct size and HMGB1 protein levels 24 h after reperfusion. CONCLUSION: The LLD of TM suppresses HMGB1-induced and TLR2-mediated myocardial reperfusion injury and apoptosis in vitro and in vivo.


Subject(s)
Apoptosis/physiology , HMGB1 Protein/metabolism , Myocardial Reperfusion Injury/metabolism , Myocytes, Cardiac/metabolism , Signal Transduction , Thrombomodulin/metabolism , Toll-Like Receptor 2/metabolism , Animals , Cells, Cultured , Inflammation/genetics , Inflammation/metabolism , Mice , Myocardial Reperfusion Injury/genetics , Myocardium/metabolism , Signal Transduction/genetics , Signal Transduction/physiology , Thrombomodulin/genetics
2.
Eur J Anaesthesiol ; 29(4): 204-7, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22343608

ABSTRACT

CONTEXT: Airway management in children suffering from mucopolysaccharidosis 1 (Hurler syndrome) remains challenging despite advances in both treatment and airway management techniques. OBJECTIVES: Forty-one anaesthetic charts following ten children over a 6-year period (2004-2010) were reviewed with emphasis on airway problems. RESULTS: All children had early stem cell transplantation at the age of 2 years or earlier. Mean (SD) age was 5 (4.3) years. Mask ventilation was difficult in five of 41 (12%) anaesthetics or in three of ten children. There were 29 intubations. Direct laryngoscopy was described as difficult (Cormack and Lehane ≥3) on 11 occasions in five of ten children. There were three of 26 (12%) failed intubations with direct laryngoscopy. These situations were resolved by a fibre-optic procedure, by laryngeal mask airway (LMA) insertion or by use of a videolaryngoscope. A laryngeal mask airway was used 11 times to avoid invasive airway management and once when direct laryngoscopy was impossible. CONCLUSION: The airway management of children with mucopolysaccharidosis 1 remains critical, despite advances in both treatment and airway management techniques. Problems did not seem to increase as children grew older. We assume that technical improvements such as standardised use of the laryngeal mask airway or attached tube channel videolaryngoscopes as well as a stem cell transplantation treatment of the disease helped the management of older children with mucopolysaccharidosis 1.


Subject(s)
Airway Management/methods , Intubation, Intratracheal/methods , Laryngoscopy/methods , Mucopolysaccharidosis I/surgery , Age Factors , Child , Child, Preschool , Female , Fiber Optic Technology , Humans , Infant , Laryngeal Masks , Laryngoscopes , Male , Mucopolysaccharidosis I/therapy , Retrospective Studies , Stem Cell Transplantation/methods , Video-Assisted Surgery
3.
Cardiovasc Res ; 92(1): 123-31, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21632883

ABSTRACT

AIMS: Myocardial infarction (MI) results in acute impairment of left ventricular (LV) function through the initial development of cardiomyocyte death and subsequent progression of LV remodelling. The expression of syndecan-4 (Sdc4), a transmembrane proteoglycan, is up-regulated after MI, but its function in the heart remains unknown. Here, we characterize the effects of Sdc4 deficiency in murine myocardial ischaemia and permanent infarction. METHODS AND RESULTS: Targeted deletion of Sdc4 (Sdc4(-/-)) leads to increased myocardial damage after ischaemic-reperfusion injury due to enhanced cardiomyocyte apoptosis associated with reduced activation of extracellular signal-regulated kinase in cardiomyocytes in vitro and in vivo. After ischaemic-reperfusion injury and permanent infarction, we observed an increase in cardiomyocyte area, nuclear translocation of nuclear factor of activated T cells (NFAT), and transcription of the NFAT target rcan1.4 in wild-type mice. NFAT pathway activation was enhanced in Sdc4(-/-) mice. In line with the in vivo data, NFAT activation and hypertrophy occurs in isolated cardiomyocytes with reduced Sdc4 expression during phenylephrine stimulation in vitro. Despite the initially increased myocardial damage, echocardiography revealed improved LV geometry and function in Sdc4(-/-) mice 7 days after MI. CONCLUSION: Interception of the Sdc4 pathway enhances infarct expansion and hypertrophic remodelling during early infarct healing in ischaemic-reperfusion injury and permanent infarction mouse models and exerts net beneficial effects on LV function.


Subject(s)
Apoptosis , Myocardial Reperfusion Injury/prevention & control , Myocardium/pathology , NFATC Transcription Factors/physiology , Signal Transduction/physiology , Syndecan-4/physiology , Ventricular Remodeling , Animals , Cardiomegaly/etiology , Cells, Cultured , Mice , Mice, Inbred C57BL , Myocardial Infarction/pathology , Myocytes, Cardiac/pathology , Rats , Rats, Sprague-Dawley , Syndecan-4/deficiency , Ventricular Function, Left , p38 Mitogen-Activated Protein Kinases/physiology
4.
Anesthesiology ; 113(3): 610-8, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20693875

ABSTRACT

BACKGROUND: Inflammation is characterized by leukocyte recruitment. Macrophages and neutrophils contribute to tissue damage and organ dysfunction. Modulating leukocyte invasion can protect from these adverse effects. Leukocyte recruitment critically depends on the urokinase-type plasminogen activator receptor (u-PAR). We here use a novel technique to longitudinally quantify cell trafficking in inflammatory models in live animals. METHODS: Near-infrared fluorophore-labeled leukocytes were adoptively transferred to mice with thioglycollate peritonitis to study leukocyte trafficking to sites of inflammation. Macrophage and neutrophil trafficking was followed with three-dimensional fluorescence-mediated-tomography. u-PAR-/- and wild-type macrophage recruitment was studied by cross-over adoptive cell transfer to elucidate the role of leukocytic versus u-PAR expressed on other cells. Endotoxic shock-induced pulmonary inflammation was used to study u-PARs role for pulmonary neutrophil recruitment. RESULTS: Mice experiencing peritonitis showed a significant increase in mean fluorescence intensity because of enhanced macrophage (315%, n=9-10), P<0.05) or neutrophil (194%, n=6, P<0.02) recruitment. Fluorescence-mediated-tomography uncovered a macrophage recruitment defect in the peritonitis model for u-PAR-/- mice (147% of baseline) compared with control mice (335% of baseline, n=8-9, P<0.05). When u-PAR-/--macrophages were transferred to wild-type mice fluorescence intensity increased to 145% while wild-type macrophage transfer into u-PAR-/- resulted in 192% increase compared with baseline (n=6, P<0.05). Reduced neutrophil recruitment in pulmonary inflammation in u-PAR-/- mice was accompanied by improved pulmonary gas exchange. CONCLUSION: Using noninvasive in vivo fluorescence-mediated tomography to image leukocyte recruitment in inflammatory mouse models, we describe a novel macrophage recruitment defect in u-PAR-/- mice. Targeting u-PAR for modulation of leukocyte recruitment is a promising therapeutic strategy to ameliorate leukocyte induced tissue damage.


Subject(s)
Cell Movement/physiology , Fluoresceins , Inflammation Mediators/physiology , Macrophages, Peritoneal/pathology , Neutrophil Infiltration/physiology , Peritonitis/pathology , Receptors, Urokinase Plasminogen Activator/physiology , Tomography , Animals , Cell Line, Transformed , Cell Movement/genetics , Endothelium, Vascular/cytology , Endothelium, Vascular/pathology , Endothelium, Vascular/physiology , Fluoresceins/metabolism , Fluorescent Dyes/metabolism , Macrophages, Peritoneal/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Peritonitis/metabolism , Protein Transport/physiology , Receptors, Urokinase Plasminogen Activator/deficiency , Receptors, Urokinase Plasminogen Activator/genetics , Tomography/methods
5.
Anesthesiology ; 110(5): 1041-9, 2009 May.
Article in English | MEDLINE | ID: mdl-19352171

ABSTRACT

BACKGROUND: Perioperative myocardial ischemia poses a vital threat to surgical patients. Means to protect postischemic myocardium are clinically not available. Lidocaine has been demonstrated to exert antiinflammatory pleiotropic effects. The authors set out to test if lidocaine protects ischemic myocardium from reperfusion injury. METHOD: A mouse model of transient coronary artery ligation (30 min) and reperfusion (24 h) was used with animal care committee approval. Infarct size and area-at-risk were determined. Leukocyte recruitment was quantified on immunohistochemical stainings. Apoptosis was assessed using enzyme-linked immunosorbent assay to detect histone modifications and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. Lidocaine effects on leukocyte-endothelial interactions were assessed in vitro by using a parallel-plate flow chamber or static adhesion assays. RESULTS: Infarct size per area-at-risk was reduced by 27% in mice treated with a lidocaine bolus (1 mg/kg) before a continuous infusion (0.6 mg . kg(-1) . h(-1)) during ischemia (P < 0.005). Neutrophil density in the infarct and periinfarct zone was not reduced by lidocaine, although the size of the infiltrated area was. Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cardiomyocytes and endothelial cells were significantly reduced in the periinfarct zone by lidocaine. In vitro, no effect on leukocyte rolling or firm adhesion to resting or activated endothelium was demonstrable. In vitro, lidocaine reduced cardiomyocyte apoptosis induced by hypoxia and reoxygenation (3h/1h) significantly. Infarct size and in vitro cardiomyocyte apoptosis were likewise reduced when lidocaine bolus and infusion were administered after the ischemic insult. CONCLUSION: Lidocaine exerts cardioprotective effects when administered before or after the ischemic insult. This effect is mediated through an antiapoptotic and not through an antiinflammatory pathway and may be therapeutically exploitable.


Subject(s)
Apoptosis/drug effects , Cardiotonic Agents/therapeutic use , Lidocaine/therapeutic use , Myocardial Ischemia/drug therapy , Myocardial Reperfusion Injury/prevention & control , Animals , Apoptosis/physiology , Cardiotonic Agents/pharmacology , Lidocaine/pharmacology , Mice , Myocardial Ischemia/complications , Myocardial Ischemia/pathology , Myocardial Reperfusion Injury/etiology , Myocardial Reperfusion Injury/pathology , Myocardium/pathology
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