title: Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo.
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.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Üllen
authors.forename: Evelin
authors.initials: E
authors.lastname: Singewald
authors.forename: Viktoria
authors.initials: V
authors.lastname: Konya
authors.forename: Günter
authors.initials: G
authors.lastname: Fauler
authors.forename: Helga
authors.initials: H
authors.lastname: Reicher
authors.forename: Christoph
authors.initials: C
authors.lastname: Nusshold
authors.forename: Astrid
authors.initials: A
authors.lastname: Hammer
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
authors.forename: Peter
authors.initials: P
authors.lastname: Holzer
authors.forename: Ernst
authors.initials: E
authors.lastname: Malle
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sattler
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D055806:Microvessels / Q000166:cytology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D009195:Peroxidase / Q000172:deficiency / Q000378:metabolism*; D010955:Plasmalogens / Q000378:metabolism; D051381:Rats; D013552:Swine
chemical_list: C432398:2-chlorohexadecanal; D000447:Aldehydes; D005227:Fatty Acids; D008070:Lipopolysaccharides; D016877:Oxidants; D010955:Plasmalogens; C001634:fatty aldehyde; D009195:Peroxidase; D048056:Mitogen-Activated Protein Kinase 9; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8