Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
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
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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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- Abstract:
- 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
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