Paul Robert, Angele Barbara, Popp Bernadette, Klein Matthias, Riedel Eva, Pfister Hans-Walter, Koedel Uwe
Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Marchioninistr. 15, D-81377 Munich, Germany.
Exp Neurol. 2007 Jan;203(1):158-67. doi: 10.1016/j.expneurol.2006.08.003. Epub 2006 Sep 28.
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.
血管通透性增加导致血管源性脑水肿是许多急性神经系统疾病的特征，如中风、脑外伤和脑膜炎。Src家族激酶，尤其是c-Src，在响应VEGF调节血脑屏障通透性方面发挥重要作用，但也介导白细胞功能和细胞因子信号传导。在这里，我们证明，尽管通过蛋白质阵列分析确定炎症趋化因子如IL-6、CCL-9、CXCL-1、CXCL-2和G-CSF在大脑中的表达增加，但在实验性肺炎球菌脑膜炎期间，Src的药理学抑制或c-Src缺乏并不影响脑脊液（CSF）细胞增多、脑水肿形成和细菌生长。相反，在冷诱导的脑损伤中，抑制Src可显著减少脑水肿形成、病变体积和临床恶化，而不会降低细胞因子/趋化因子表达。虽然脑外伤与大脑VEGF形成增加有关，但在肺炎球菌脑膜炎期间VEGF水平显著下降。因此，我们得出结论，在脑外伤中，血脑屏障的紧密性由VEGF/Src途径调节，而c-Src在细菌性脑膜炎期间不影响脑水肿形成和白细胞功能。
