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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Üllen, A; Singewald, E; Konya, V; Fauler, G; Reicher, H; Nusshold, C; Hammer, A; Kratky, D; Heinemann, A; Holzer, P; Malle, E; Sattler, W.
Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo.
PLoS One. 2013; 8(5):e64034-e64034 Doi: 10.1371/journal.pone.0064034 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Sattler Wolfgang
Üllen Andreas
Co-Autor*innen der Med Uni Graz
Fauler Günter
Hammer Astrid
Heinemann Akos
Hinteregger Helga
Holzer Peter
Konya Viktoria
Kratky Dagmar
Malle Ernst
Nusshold Christoph
Singewald Evelin

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Peripheral leukocytes can exacerbate brain damage by release of cytotoxic mediators that disrupt blood-brain barrier (BBB) function. One of the oxidants released by activated leukocytes is hypochlorous acid (HOCl) formed via the myeloperoxidase (MPO)-H2O2-Cl(-) system. In the present study we examined the role of leukocyte activation, leukocyte-derived MPO and MPO-generated oxidants on BBB function in vitro and in vivo. In a mouse model of lipopolysaccharide (LPS)-induced systemic inflammation, neutrophils that had become adherent released MPO into the cerebrovasculature. In vivo, LPS-induced BBB dysfunction was significantly lower in MPO-deficient mice as compared to wild-type littermates. Both, fMLP-activated leukocytes and the MPO-H2O2-Cl(-) system inflicted barrier dysfunction of primary brain microvascular endothelial cells (BMVEC) that was partially rescued with the MPO inhibitor 4-aminobenzoic acid hydrazide. BMVEC treatment with the MPO-H2O2-Cl(-) system or activated neutrophils resulted in the formation of plasmalogen-derived chlorinated fatty aldehydes. 2-chlorohexadecanal (2-ClHDA) severely compromised BMVEC barrier function and induced morphological alterations in tight and adherens junctions. In situ perfusion of rat brain with 2-ClHDA increased BBB permeability in vivo. 2-ClHDA potently activated the MAPK cascade at physiological concentrations. An ERK1/2 and JNK antagonist (PD098059 and SP600125, respectively) protected against 2-ClHDA-induced barrier dysfunction in vitro. The current data provide evidence that interference with the MPO pathway could protect against BBB dysfunction under (neuro)inflammatory conditions.
Find related publications in this database (using NLM MeSH Indexing)
Aldehydes - pharmacology
Animals -
Blood-Brain Barrier - drug effects
Endothelial Cells - cytology
Fatty Acids - biosynthesis
Humans -
Lipopolysaccharides - pharmacology
Male -
Mice -
Microvessels - cytology
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
Mitogen-Activated Protein Kinase 8 - metabolism
Mitogen-Activated Protein Kinase 9 - metabolism
Neutrophils - drug effects
Oxidants - metabolism
Peroxidase - deficiency
Plasmalogens - metabolism
Rats -
Swine -

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