Vascular endothelial growth factor is increased in cerebrospinal fluid after traumatic brain injury in infants and children

被引:57
作者
Shore, PM
Jackson, EK
Wisniewski, SR
Clark, RSB
Adelson, PD
Kochanek, PM
机构
[1] Univ Pittsburgh, Sch Med, Dept Crit Care Med, Pittsburgh, PA USA
[2] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA
[3] Univ Pittsburgh, Dept Pharmacol, Pittsburgh, PA 15261 USA
[4] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA
[5] Childrens Hosp Pittsburgh, Dept Neurosurg, Pittsburgh, PA 15213 USA
关键词
adenosine; angiogenesis; child abuse; head injury; head trauma; pediatrics; purine; regeneration;
D O I
10.1227/01.NEU.0000108642.88724.DB
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
OBJECTIVE: Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis, the formation of which is triggered by hypoxia, cytokines, and growth factors and is also induced by activation of the adenosine 2B receptor. VEGF is neuroprotective in several models of experimental brain injury and is increased in brain after traumatic brain injury (TBI) in humans and experimental animals. Adenosine is a neuroprotective purine metabolite that increases in cerebrospinal fluid (CSF) after clinical TBI in children. We hypothesized that VEGF levels would 1) be increased in CSF after TBI in infants and children, and 2) be preceded by increases in CSF adenosine. To test this hypothesis, we designed a case-control study to compare the CSF of infants and children after severe TBI with that of uninjured children. METHODS: Using an Institutional Review Board-approved protocol, we compared CSF concentrations of VEGF (by enzyme-linked immunosorbent assay) and adenosine (by high-performance liquid chromatography) in 73 samples from 14 infants and children with severe TBI (Glasgow Coma Scale score less than or equal to8) with those in CSF from 5 noninjured control subjects. Patients received standard neurointensive care. RESULTS: Mean VEGF levels were increased after TBI versus control (39.8 +/- 6.2 versus 14.9 +/- 1.5 ng/dl, mean +/- standard error of the mean, P = 0.0002) and peaked at 91.6 +/- 26.4 ng/dl, approximately 6 times control (P = 0.001). Peak VEGF occurred at 22.4 hours after injury. There was a trend toward increased adenosine concentration after TBI versus control (18.3 +/- 3.5 versus 11.5 +/- 2.3 nmol/L), but this did not reach statistical significance. A multivariate regression model showed an independent, significant association between the concentrations of VEGF and adenosine. CONCLUSION: VEGF is increased in CSF after pediatric TBI, and this increase is associated with an increase in CSF adenosine. These results may imply that a component of the vascular regenerative response of the brain is initiated rapidly after TBI and continues for several days after injury. Further investigation is warranted to determine 1) whether this association is causative, 2) the role of adenosine in triggering the increase in CSF VEGF concentration, and 3) the exact role VEGF that plays after injury.
引用
收藏
页码:605 / 611
页数:7
相关论文
共 55 条
[21]   Adenosine upregulates VEGF expression in cultured myocardial vascular smooth muscle cells [J].
Gu, JW ;
Brady, AL ;
Anand, V ;
Moore, MC ;
Kelly, WC ;
Adair, TH .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 1999, 277 (02) :H595-H602
[22]   Intraventricular infusion of vascular endothelial growth factor promotes cerebral angiogenesis with minimal brain edema [J].
Harrigan, MR ;
Ennis, SR ;
Masada, T ;
Keep, RF .
NEUROSURGERY, 2002, 50 (03) :589-598
[23]   Reduction of ischemic damage by application of vascular endothelial growth factor in rat brain after transient ischemia [J].
Hayashi, T ;
Abe, K ;
Itoyama, Y .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 1998, 18 (08) :887-895
[24]  
Jackson EK, 1996, J PHARMACOL EXP THER, V279, P1250
[25]   Vascular endothelial growth factor:: Direct neuroprotective effect in in vitro ischemia [J].
Jin, KL ;
Mao, XO ;
Greenberg, DA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (18) :10242-10247
[26]   Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide [J].
Kimura, H ;
Weisz, A ;
Kurashima, Y ;
Hashimoto, K ;
Ogura, T ;
D'Acquisto, F ;
Addeo, R ;
Makuuchi, M ;
Esumi, H .
BLOOD, 2000, 95 (01) :189-197
[27]  
Kochanek Patrick M., 2000, Pediatr Crit Care Med, V1, P4, DOI 10.1097/00130478-200007000-00003
[28]  
Kochanek PM, 2001, HEAD TRAUMA, P141
[29]   Transient coexpression of nestin, GFAP, and vascular endothelial growth factor in mature reactive astroglia following neural grafting or brain wounds [J].
Krum, JM ;
Rosenstein, JM .
EXPERIMENTAL NEUROLOGY, 1999, 160 (02) :348-360
[30]   Angiogenic and astroglial responses to vascular endothelial growth factor administration in adult rat brain [J].
Krum, JM ;
Mani, N ;
Rosenstein, JM .
NEUROSCIENCE, 2002, 110 (04) :589-604