Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency.
Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency.
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发表时间：
2000-01
期刊：
影响因子：
11.2
通讯作者：
L. Peña;Z. Fuks;R. Kolesnick
中科院分区：
文献类型：
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作者：
L. Peña;Z. Fuks;R. Kolesnick
电离辐射对中枢神经系统（CNS）的损伤可能是血管内皮损伤的结果。最近的研究表明，辐射诱导的体外和体内肺内皮细胞凋亡是由脂质第二信使神经酰胺通过激活酸性鞘磷脂酶（ASM）介导的。这种对辐射的细胞凋亡反应可以通过碱性成纤维细胞生长因子或 ASM 的基因突变来抑制。在中枢神经系统中，单剂量辐射已被证明会导致 24 小时内内皮细胞损失 15%，但这种损失是否与细胞凋亡有关仍不清楚。在本研究中，在 C57BL/6 小鼠 CNS 中观察到剂量和时间依赖性的细胞凋亡诱导。通过末端脱氧核苷酸转移酶介导的切口末端标记来定量细胞凋亡，并通过末端脱氧核苷酸转移酶介导的切口末端标记和番茄凝集素的组织化学双重标记来测定特异性内皮细胞凋亡。从单剂量放射后 4 小时开始，细胞凋亡持续 24 小时，并在 12 小时达到峰值，发生率为脊髓切片中总细胞的 0.7-1.4%。高达 20% 的凋亡细胞是内皮细胞。这种效应也出现在大脑的多个区域（延髓、脑桥和海马体）。静脉注射后观察到辐射诱导的细胞凋亡显着减少。碱性成纤维细胞生长因子治疗（0.45-4.5微克/小鼠）。在 C3H/HeJ 小鼠中也观察到相同的结果。此外，经过辐射的 ASM 基因敲除小鼠的内皮细胞凋亡减少了 70%。这项研究表明，电离辐射会诱导整个中枢神经系统的早期内皮细胞凋亡。这些数据与最近将辐射引起的应激与神经酰胺联系起来的证据一致，并提出了改变细胞凋亡反应以控制中枢神经系统辐射毒性的方法。
Injury to the central nervous system (CNS) by ionizing radiation may be a consequence of damage to the vascular endothelium. Recent studies showed that radiation-induced apoptosis of endothelial cells in vitro and in the lung in vivo is mediated by the lipid second messenger ceramide via activation of acid sphingomyelinase (ASM). This apoptotic response to radiation can be inhibited by basic fibroblast growth factor or by genetic mutation of ASM. In the CNS, single-dose radiation has been shown to result in a 15% loss of endothelial cells within 24 h, but whether or not this loss is associated with apoptosis remains unknown. In the present studies, dose- and time-dependent induction of apoptosis was observed in the C57BL/6 mouse CNS. Apoptosis was quantified by terminal deoxynucleotidyl transferase-mediated nick end labeling, and specific endothelial apoptosis was determined by histochemical double labeling with terminal deoxynucleotidyl transferase-mediated nick end labeling and Lycopersicon esculentum lectin. Beginning at 4 h after single-dose radiation, apoptosis was ongoing for 24 h and peaked at 12 h at an incidence of 0.7-1.4% of the total cells in spinal cord sections. Up to 20% of the apoptotic cells were endothelial. This effect was also seen in multiple regions of the brain (medulla, pons, and hippocampus). A significant reduction of radiation-induced apoptosis was observed after i.v. basic fibroblast growth factor treatment (0.45-4.5 microg/mouse). Identical results were noted in C3H/HeJ mice. Furthermore, irradiated ASM knockout mice displayed as much as a 70% reduction in endothelial apoptosis. This study demonstrates that ionizing radiation induces early endothelial cell apoptosis throughout the CNS. These data are consistent with recent evidence linking radiation-induced stress with ceramide and suggest approaches to modify the apoptotic response in control of radiation toxicity in the CNS.