Differential regulation of blood-brain barrier permeability in brain trauma and pneumococcal meningitis-role of Src kinases.
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.
Paul
Robert
R
Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Marchioninistr. 15, D-81377 Munich, Germany. Robert.Paul@med.uni-muenchen.de
Angele
Barbara
B
Popp
Bernadette
B
Klein
Matthias
M
Riedel
Eva
E
Pfister
Hans-Walter
HW
Koedel
Uwe
U
D000818:Animals; D001812:Blood-Brain Barrier / Q000201:enzymology* / Q000382:microbiology / Q000503:physiopathology; D001929:Brain Edema / Q000201:enzymology* / Q000382:microbiology / Q000503:physiopathology; D001930:Brain Injuries / Q000201:enzymology* / Q000503:physiopathology; D000081247:CSK Tyrosine-Protein Kinase; D002536:Cerebral Arteries / Q000201:enzymology* / Q000382:microbiology / Q000503:physiopathology; D002555:Cerebrospinal Fluid / Q000187:drug effects / Q000378:metabolism; D015170:Cerebrospinal Fluid Pressure / Q000187:drug effects / Q000502:physiology; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004660:Encephalitis / Q000276:immunology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008586:Meningitis, Pneumococcal / Q000201:enzymology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018925:Chemokines; D004791:Enzyme Inhibitors; D042461:Vascular Endothelial Growth Factor A; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases