Abstract
Increased vascular permeability causing vasogenic brain edema is characteristic for many acute neurological diseases such as stroke, brain trauma, and meningitis. Src family kinases, especially c-Src, play an important role in regulating blood-brain barrier permeability in response to VEGF, but also mediate leukocyte function and cytokine signalling. Here we demonstrate that pharmacological inhibition of Src or c-Src deficiency does not influence cerebrospinal fluid (CSF) pleocytosis, brain edema formation, and bacterial outgrowth during experimental pneumococcal meningitis despite the increased cerebral expression of inflammatory chemokines, such as IL-6, CCL-9, CXCL-1, CXCL-2 and G-CSF as determined by protein array analysis. In contrast, inhibition of Src significantly reduced brain edema formation, lesion volume, and clinical worsening in cold-induced brain injury without decreasing cytokine/chemokine expression. While brain trauma was associated with increased cerebral VEGF formation, VEGF levels significantly declined during pneumococcal meningitis. Therefore, we conclude that in brain trauma blood-brain barrier tightness is regulated by the VEGF/Src pathway whereas c-Src does not influence brain edema formation and leukocyte function during bacterial meningitis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood-Brain Barrier / enzymology*
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Blood-Brain Barrier / microbiology
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Blood-Brain Barrier / physiopathology
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Brain Edema / enzymology*
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Brain Edema / microbiology
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Brain Edema / physiopathology
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Brain Injuries / enzymology*
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Brain Injuries / physiopathology
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CSK Tyrosine-Protein Kinase
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Cerebral Arteries / enzymology*
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Cerebral Arteries / microbiology
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Cerebral Arteries / physiopathology
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Cerebrospinal Fluid / drug effects
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Cerebrospinal Fluid / metabolism
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Cerebrospinal Fluid Pressure / drug effects
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Cerebrospinal Fluid Pressure / physiology
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Chemokines / immunology
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Chemokines / metabolism
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Disease Models, Animal
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Encephalitis / immunology
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Encephalitis / physiopathology
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Enzyme Inhibitors / pharmacology
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Meningitis, Pneumococcal / enzymology*
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Meningitis, Pneumococcal / physiopathology
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Mice
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Mice, Inbred C57BL
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins pp60(c-src) / antagonists & inhibitors
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Proto-Oncogene Proteins pp60(c-src) / metabolism
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Vascular Endothelial Growth Factor A / immunology
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Vascular Endothelial Growth Factor A / metabolism
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / metabolism*
Substances
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Chemokines
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Enzyme Inhibitors
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Vascular Endothelial Growth Factor A
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Protein-Tyrosine Kinases
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CSK Tyrosine-Protein Kinase
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Proto-Oncogene Proteins pp60(c-src)
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src-Family Kinases