Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo.
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 examin...
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0064034&type=printable |
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| author | Andreas Üllen Evelin Singewald Viktoria Konya Günter Fauler Helga Reicher Christoph Nusshold Astrid Hammer Dagmar Kratky Akos Heinemann Peter Holzer Ernst Malle Wolfgang Sattler |
| author_facet | Andreas Üllen Evelin Singewald Viktoria Konya Günter Fauler Helga Reicher Christoph Nusshold Astrid Hammer Dagmar Kratky Akos Heinemann Peter Holzer Ernst Malle Wolfgang Sattler |
| author_sort | Andreas Üllen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d955f3eaaa054e97b4cb5f1aeadeebac |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-d955f3eaaa054e97b4cb5f1aeadeebac2025-08-20T03:26:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0185e6403410.1371/journal.pone.0064034Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo.Andreas ÜllenEvelin SingewaldViktoria KonyaGünter FaulerHelga ReicherChristoph NussholdAstrid HammerDagmar KratkyAkos HeinemannPeter HolzerErnst MalleWolfgang SattlerPeripheral 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0064034&type=printable |
| spellingShingle | Andreas Üllen Evelin Singewald Viktoria Konya Günter Fauler Helga Reicher Christoph Nusshold Astrid Hammer Dagmar Kratky Akos Heinemann Peter Holzer Ernst Malle Wolfgang Sattler Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo. PLoS ONE |
| title | Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo. |
| title_full | Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo. |
| title_fullStr | Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo. |
| title_full_unstemmed | Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo. |
| title_short | Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo. |
| title_sort | myeloperoxidase derived oxidants induce blood brain barrier dysfunction in vitro and in vivo |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0064034&type=printable |
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