Vascular Endothelial Growth Factor and Blood-Brain Barrier Disruption in Tuberculous Meningitis

Utrecht University, Utrecht, Utrecht, Netherlands
The Pediatric Infectious Disease Journal (Impact Factor: 2.72). 08/2004; 23(7):608-13. DOI: 10.1097/01.inf.0000131634.57368.45
Source: PubMed


Tuberculous meningitis (TBM) is characterized by disruption of the blood-brain barrier (BBB), cerebral edema and increased intracranial pressure (ICP). Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor and a mediator of brain edema.
To investigate whether in children with TBM disruption of the BBB relates to VEGF production and to assess the effect of corticosteroids on Mycobacterium tuberculosis-induced VEGF production by mononuclear leukocytes.
Blood and CSF samples were collected from 26 children with stage 2-3 TBM and 20 controls. All patients received antituberculous and adjuvant corticosteroid therapy. Children were evaluated by ICP recording, computerized tomography scanning and outcome assessment at 6 months follow-up. BBB disruption was quantified by cerebrospinal fluid (CSF)-serum albumin ratios. VEGF concentrations were measured by enzyme-linked immunosorbent assay. In vitro human monocytic THP-1 cells were stimulated with M. tuberculosis sonicate or culture supernatant, and VEGF production was measured in the presence or absence of corticosteroids.
CSF VEGF concentrations were significantly higher in TBM patients than in the controls and correlated with mononuclear cell counts (r = 0.64; P = 0.001) and CSF-serum albumin ratio (r = 0.49; P = 0.015). CSF VEGF did not significantly correlate with elevated ICP. In vitro induction of VEGF production by M. tuberculosis sonicate or culture supernatant could be completely abrogated by corticosteroid treatment.
Inflammatory cells secrete VEGF during TBM. CSF VEGF correlates with BBB disruption. Inhibition of VEGF may explain part of the clinical effect of adjuvant corticosteroid therapy in TBM.

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    • "VEGF-mediated neovascularization may enhance the oxygen supply. Besides, VEGF that is produced intrathecally may contribute to disruption of the blood-brain barrier (BBB)9,32). Thus, the bacteria introduced at the monent of VP shunt surgery may easily break into the brain tissue and vascular channels through the disrupted BBB and the increased vascular networks probably provide nutrients and oxygen to the bacteria. "
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    • "Greater antigen-stimulated levels of VEGF in combination with other cytokines in the supernatant of interferon-γ release assays were found to accurately differentiate active disease from latent TB infection in one study [40]. Furthermore, increased VEGF levels in plasma and/or CSF were found to correlate with activity in neurotuberculosis [23], [24], [41]. However, it is unlikely that local (i.e., aqueous or vitreous) VEGF levels can serve as a biomarker of active intraocular TB since VEGF expression may be upregulated as a result of many different posterior segment inflammatory conditions [42], [43]. "
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    PLoS ONE 12/2011; 6(12):e28383. DOI:10.1371/journal.pone.0028383 · 3.23 Impact Factor
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    • "Loss of BBB structural integrity and function plays a pivotal role in the pathogenesis of many diseases of the central nervous system (CNS). The BBB is altered in many clinical settings including brain trauma (Unterberg et al, 2004), focal brain ischemia (Latour et al, 2004), meningitis (van der et al, 2004), brain tumor (Lee et al, 2006), stroke (Cipolla et al, 2004), inflammation (Stamatovic et al, 2006), Alzheimer's disease (Kalaria, 1992), and multiple sclerosis (Minagar and Alexander, 2003). In ischemic brain injury, matrix metalloproteinases (MMPs) contribute to the disruption of the BBB leading to vasogenic edema, and to the influx of leukocytes into the CNS (Gasche et al, 2006). "
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