Fuks Z, Persaud R S, Alfieri A, McLoughlin M, Ehleiter D, Schwartz J L, Seddon A P, Cordon-Cardo C, Haimovitz-Friedman A
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Cancer Res. 1994 May 15;54(10):2582-90.
Apoptosis (programmed cell death) serves as a common mechanism of interphase cell death after radiation exposure in thymic, lymphoid, and hematopoietic cells but has infrequently been documented in other adult mammalian cell types. The present study demonstrates that apoptotic interphase cell death occurs in endothelial cells after exposure to clinically relevant radiation doses and that basic fibroblast growth factor (bFGF) protects endothelial cells against this mode of the lethal effects of radiation. Radiation exposure produced heterologous double-stranded DNA breaks in endothelial cells, but the cells exhibited a similar competence for repair of this damage in the presence or absence of bFGF. However, subsequent to the completion of this repair process, a second process of DNA fragmentation became apparent, which was detected only in the absence of bFGF and was associated with a DNA ladder of oligonucleosomal fragments characteristic of apoptosis. The apoptotic DNA degradation occurred mainly in G0-G1 phase cells and was inhibited by bFGF stimulation. C3H/HeJ mice exposed to lethal doses of whole lung irradiation exhibited similar apoptotic changes in the endothelial cell lining of the pulmonary microvasculature within 6-8 h after radiation exposure. bFGF given i.v. immediately before and after irradiation inhibited the development of apoptosis in these cells and protected mice against the development of lethal radiation pneumonitis. These findings suggest that interphase apoptosis may represent a biologically relevant mechanism of radiation-induced cell kill in nonlymphoid mammalian cells both in vitro and in vivo and that natural protection mechanisms against this effect may be associated with the level of radiation resistance in normal and malignant tissues in vivo.
凋亡（程序性细胞死亡）是胸腺、淋巴和造血细胞受辐射后间期细胞死亡的常见机制，但在其他成年哺乳动物细胞类型中鲜有记录。本研究表明，临床相关辐射剂量照射后，内皮细胞会发生凋亡性间期细胞死亡，且碱性成纤维细胞生长因子（bFGF）可保护内皮细胞免受这种辐射致死效应的影响。辐射照射在内皮细胞中产生异源双链DNA断裂，但无论有无bFGF，细胞修复这种损伤的能力相似。然而，在该修复过程完成后，第二个DNA片段化过程变得明显，仅在没有bFGF的情况下检测到，且与凋亡特有的寡核小体片段DNA梯带相关。凋亡性DNA降解主要发生在G0-G1期细胞中，并受到bFGF刺激的抑制。接受致死剂量全肺照射的C3H/HeJ小鼠在照射后6-8小时内，肺微血管内皮细胞内衬出现类似的凋亡变化。在照射前后立即静脉注射bFGF可抑制这些细胞凋亡的发生，并保护小鼠免受致死性放射性肺炎的发展。这些发现表明，间期凋亡可能是体外和体内非淋巴细胞哺乳动物细胞中辐射诱导细胞杀伤的生物学相关机制，并且针对这种效应的天然保护机制可能与体内正常和恶性组织的辐射抗性水平相关。
