Search

Your search keyword '"Wagner, Josephin"' showing total 4 results
Start Over Author "Wagner, Josephin" Topic subarachnoid hemorrhage
4 results on '"Wagner, Josephin"'

1. Interleukin 6-Mediated Endothelial Barrier Disturbances Can Be Attenuated by Blockade of the IL6 Receptor Expressed in Brain Microvascular Endothelial Cells.

Author

Blecharz-Lang KG, Wagner J, Fries A, Nieminen-Kelhä M, Rösner J, Schneider UC, and Vajkoczy P

Subjects
Animals, Antibodies pharmacology, Antigens, CD metabolism, Cadherins metabolism, Cell Line, Transformed, Cell Proliferation, Cytokines metabolism, Disease Models, Animal, Electric Impedance, Endothelial Cells drug effects, Gene Expression Regulation drug effects, Interleukin-6 immunology, Interleukin-6 pharmacology, Magnetic Resonance Imaging, Male, Mice, Occludin metabolism, Receptors, Interleukin-6 genetics, Subarachnoid Hemorrhage diagnostic imaging, Subarachnoid Hemorrhage mortality, Blood-Brain Barrier pathology, Endothelial Cells metabolism, Endothelium, Vascular pathology, Gene Expression Regulation physiology, Interleukin-6 metabolism, Receptors, Interleukin-6 metabolism, Subarachnoid Hemorrhage pathology
Abstract

Compromised blood-brain barrier (BBB) by dysregulation of cellular junctions is a hallmark of many cerebrovascular disorders due to the pro-inflammatory cytokines action. Interleukin 6 (IL6) is implicated in inflammatory processes and in secondary brain injury after subarachnoid hemorrhage (SAH) but its role in the maintenance of cerebral endothelium still requires a precise elucidation. Although IL6 has been shown to exert pro-inflammatory action on brain microvascular endothelial cells (ECs), the expression of one of the IL6 receptors, the IL6R is controversially discussed. In attempt to reach more clarity in this issue, we present here an evident baseline expression of the IL6R in BBB endothelium in vivo and in an in vitro model of the BBB, the cEND cell line. A significantly increased expression of IL6R and its ligand was observed in BBB capillaries 2 days after experimental SAH in mice. In vitro, we saw IL6 administration resulting in an intracellular and extracellular elevation of IL6 protein, which was accompanied by a reduced expression of tight and adherens junctions, claudin-5, occludin, and vascular-endothelial (VE-) cadherin. By functional assays, we could demonstrate IL6-incubated brain ECs to lose their endothelial integrity that can be attenuated by inhibiting the IL6R. Blockade of the IL6R by a neutralizing antibody has reconstituted the intercellular junction expression to the control level and caused a restoration of the transendothelial electrical resistance of the cEND cell monolayer. Our findings add depth to the current understanding of the involvement of the endothelial IL6R in the loss of EC integrity implicating potential therapy options.

Published
2018
Full Text
View/download PDF

2. Intravascular Inflammation Triggers Intracerebral Activated Microglia and Contributes to Secondary Brain Injury After Experimental Subarachnoid Hemorrhage (eSAH).

Author

Atangana E, Schneider UC, Blecharz K, Magrini S, Wagner J, Nieminen-Kelhä M, Kremenetskaia I, Heppner FL, Engelhardt B, and Vajkoczy P

Subjects
Animals, Brain blood supply, Brain metabolism, Cell Death, Cell Movement, Disease Models, Animal, Encephalitis metabolism, Endothelium, Vascular physiology, Female, Hemodynamics, Immunity, Innate, Leukocytes physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Microvessels metabolism, Neutrophils physiology, Subarachnoid Hemorrhage metabolism, Brain physiopathology, Encephalitis physiopathology, Intercellular Adhesion Molecule-1 metabolism, Microglia physiology, P-Selectin metabolism, Subarachnoid Hemorrhage physiopathology
Abstract

Activation of innate immunity contributes to secondary brain injury after experimental subarachnoid hemorrhage (eSAH). Microglia accumulation and activation within the brain has recently been shown to induce neuronal cell death after eSAH. In isolated mouse brain capillaries after eSAH, we show a significantly increased gene expression for intercellular adhesion molecule-1 (ICAM-1) and P-selectin. Hence, we hypothesized that extracerebral intravascular inflammatory processes might initiate the previously reported microglia accumulation within the brain tissue. We therefore induced eSAH in knockout mice for ICAM-1 (ICAM-1 -/- ) and P-selectin glycoprotein ligand-1 (PSGL-1 -/- ) to find a significant decrease in neutrophil-endothelial interaction within the first 7 days after the bleeding in a chronic cranial window model. This inhibition of neutrophil recruitment to the endothelium results in significantly ameliorated microglia accumulation and neuronal cell death in knockout animals in comparison to controls. Our results suggest an outside-in activation of the CNS innate immune system at the vessel/brain interface following eSAH. Microglia cells, as part of the brain's innate immune system, are triggered by an inflammatory reaction in the microvasculature after eSAH, thus contributing to neuronal cell death. This finding offers a whole range of new research targets, as well as possible therapy options for patients suffering from eSAH.

Published
2017
Full Text
View/download PDF

3. Endotheliale Inflammation und Zusammenbruch der Bluthirnschranke nach experimentell induzierter Subarachnoidalblutung

Author

Wagner, Josephin

Subjects
inflammation, interleukin-6, Subarachnoid hemorrhage, blood-brain barrier, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, endothelial cells
Abstract

Eine akute aneurysmatische Subarachnoidalblutung (aSAB) zählt zu den hämorrhagischen Schlaganfällen und beziffert eine jährliche Inzidenz von sechs bis elf von hunderttausend Menschen. Hauptgrund ist die Ruptur eines intrakraniellen Aneurysmas, gefolgt von einer Einblutung in den Subarachnoidalraum. Das durchschnittliche Alter bei aSAB-Patienten beträgt fünfundfünfzig Jahre und ist somit niedriger als bei Patienten mit einem ischämischen Schlaganfall. Diesbezüglich ist die sozioökonomische Belastung der aSAB vergleichsweise hoch. Mehrere Studien haben gezeigt, dass eine aSAB zu einem Zusammenbruch der Bluthirnschranke (BHS) führt, wodurch ein vasogenes Hirnödem ausgelöst wird. An Patienten nach aSAB konnte außerdem gezeigt werden, dass IL6 im Serum und im Liquor erhöht war, wobei diese Patienten ein schlechteres Outcome aufzeigten. Die frühe Hirnschädigung nach aSAB beginnt bereits nach einem initialen intrazerebralen Druckanstieg, gefolgt von einem Abfall des zerebralen Perfusionsdrucks. Experimentelle Studien widmen sich daher den Mechanismen der frühen Hirnschädigung nach aSAB mit Fokus auf Störungen der mikrovaskulären Ebene und inflammatorischen Prozessen innerhalb ZNS nach aSAB. Die hier vorgelegte Arbeit konzentrierte sich auf die Rolle des Zytokins Interleukin-6 (IL6) und seine Effekte auf die BHS nach experimenteller Subarachnoidalblutung (eSAB) in Mäusen. Um die Induktion einer eSAB an der Maus auslösen zu können, wurde die Methode der Fadenperforationstechnik angewandt. Die darauffolgenden Experimente dienten der Analyse der BHS-Eigenschaften, wobei sich nach eSAB ein deutlicher BHS-Zusammenbruch über den gesamten zeitlichen Verlauf der Experimente zeigte. Als molekulares Korrelat für den Untergang der BHS konnte die zwei wichtigsten tight junction (TJ) Moleküle Claudin-5 (Cld5) und Occludin (Ocld) identifiziert werden. Zeitgleich wurde eine Überexpression essenzieller Zytokine beobachtet. Insbesondere IL6 zeigte zu allen Zeitpunkten eine deutliche Hochregulierung an isolierten Gehirnkapillaren nach eSAB. Somit wurde nachgewiesen, dass IL6 endothelzellspezifisch in Vesikeln isolierter Gehirnkapillaren nach eSAB angereichert wird. Weiterführende In-vitro-Versuche ergaben einen deutlichen Verlust des transendothelialen Widerstandes in der cEND-Zellkultur, nachdem die Zellen mit dem rekombinanten IL6 (rIL6) behandelt wurden. Auch In vitro war ein Untergang von Cld5 und Ocld zu beobachten. Zusammenfassend zeigt diese Arbeit erstmalig die Expression von IL6 im zerebralen Endothel nach eSAB, was zeitgleich mit einem BHS-Zusammenbruch korrelierte. Abschließend soll die Rolle von IL6 in Bezug auf die frühe Hirnschädigung nach aSAB diskutiert und der Frage nachgegangen werden, ob ein Knockout von IL6 oder die externe Blockade von IL6 und seinem Rezeptor einen signifikanten Effekt auf den Pathomechanismus nach aSAB aufweist., Acute aneurysmal subarachnoid hemorrhage (aSAH) is a type of hemorrhagic stroke with an annual incidence of six to eleven out of a hundred thousand people. The main cause of an aSAH is a rupture of an intracranial aneurysm, which is followed by a bleeding into the subarachnoid space. The average age in aSAH patients is fifty-five years old, which is much younger than the average age of patients with ischemic stroke. Therefore, the socio-economic impact of aSAH is comparatively high. Numerous studies have shown, that aSAH leads to a breakdown of the blood brain barrier (BBB), causing a vasogenic brain edema. Patients with aSAH also show an increase in IL6 in serum and in cerebrospinal fluid, resulting in worse outcomes for aSAH patients. Early brain injury after aSAH occurs after an initial increase in intracerebral pressure, followed by a decrease in cerebral perfusion pressure. Therefore, current experimental studies are devoted to mechanisms of early brain damage, investigating microvascular changes and BBB breakdown with a focus on CNS inflammation after aSAH. The following work examines interleukin-6 (IL6) and its effects on the BBB after experimental subarachnoid hemorrhage (eSAH) in mice. In order to induce eSAH in mice, the filament perforation method was used. The subsequent experiments were performed to analyze BBB properties, showing a BBB breakdown over the course of the experiment. The decline of the most important tight junction (TJ) molecules Claudin-5 (Cld5) and Occludin (Ocld) caused a BBB collapse. Moreover, the overexpression of crucial cytokines was observed, while IL6 in particular was increased in isolated brain capillaries after eSAH, showing enriched expression in endothelial cells. Further in-vitro experiments revealed a significant loss of transendothelial resistance in the cEND cell culture after the cells were treated with the recombinant IL6 (rIL6). Finally, the gene expression of Cld5 and Ocld was also decreased in vitro. In summary, this work shows for the first time that IL6 is expressed in the BBB after eSAH, correlating with a BBB breakdown. The role of IL6 in relation to early brain injury after aSAH will be discussed, focusing on the effect of a knockout and an external blockade of IL6 towards the pathomechanism after aSAH.

Published
2021
Full Text
View/download PDF

4. Role of interleukin-6 in the brain endothelial dysfunction after SAH

Author

Wagner, Josephin, Blecharz, Kinga G., Schneider, Ulf, Winkler, Lars, and Vajkoczy, Peter

Subjects
Blood- Brain Barrier, ddc: 610, Interleukin- 6, Subarachnoid hemorrhage, cardiovascular diseases, 610 Medical sciences, Medicine, nervous system diseases
Abstract

Objective: Until date, mechanisms underlying the intravascular inflammatory response post subarachnoid hemorrhage (SAH) remain unclear. Interleukin-6 (IL-6) has been implicated to play a crucial role in the inflammatory response post SAH. Here, we aimed to show the time-lapse of the expression and localization[for full text, please go to the a.m. URL], 66. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

Published
2015

Catalog

Books, media, physical & digital resources
See catalog results