Antioxidants modulate induction of programmed endothelial cell death (apoptosis) by endotoxin.
Antioxidants modulate induction of programmed endothelial cell death (apoptosis) by endotoxin.
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DOI：
10.1001/archsurg.1994.01420260030003
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发表时间：
1994-02
影响因子：
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通讯作者：
P. A. Abello;S. Fidler;Gregory B. Bulkley;Timothy G. Buchman
中科院分区：
文献类型：
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作者：
P. A. Abello;S. Fidler;Gregory B. Bulkley;Timothy G. Buchman
目的探讨活性氧代谢产物作为内皮细胞凋亡信号的潜在作用。设计评价了一系列抗氧化剂对体外培养的猪主动脉内皮细胞凋亡的阻断作用。结果细胞膜通透性清除剂二甲基亚砜清除羟基自由基或铁与邻菲咯啉通过Fenton反应阻断其生成均可抑制细胞凋亡，而细胞膜不通透性清除剂超氧化物歧化酶和过氧化氢酶不能阻断细胞凋亡。用酶抑制水平的别嘌醇抑制黄嘌呤氧化酶也不能阻止细胞的凋亡，而高水平的别嘌醇在体外也能清除羟基自由基，具有保护作用。在每种情况下(二甲基亚砜、邻菲咯啉和大剂量别嘌醇)，羟基自由基消融只有在启动步骤(脂多糖)之前才有效，如果在激活步骤(热休克)之前晚些时候才有效。结论···这些发现提示了羟基自由基作为一种非致命性细胞内信号在内皮细胞凋亡中的新作用。此外，这些结果支持程序性细胞死亡在多器官功能障碍综合征发病机制中的作用，并为外科重症监护病房中最常见的死亡原因的预防和治疗提出了新的策略。
OBJECTIVE To evaluate the potential role of reactive oxygen metabolites as signals for endothelial cell apoptosis. DESIGN A series of antioxidants were evaluated for their ability to block apoptosis in cultured porcine aortic endothelial cells in vitro. RESULTS Scavenging of the hydroxyl radical with the membrane-permeable scavenger dimethyl sulfoxide or blocking its generation via the Fenton reaction by the chelation of iron with o-phenanthroline blocked apoptosis, whereas the cell membrane-impermeable scavengers superoxide dismutase and catalase did not block apoptosis. Inhibition of xanthine oxidase with enzyme-inhibitory levels of allopurinol also failed to block apoptosis, whereas high levels of allopurinol, which also scavenge the hydroxyl radical in vitro, conferred protection. In each case (dimethyl sulfoxide, o-phenanthroline, and high-dose allopurinol), hydroxyl radical ablation was only effective when administered before the priming step (lipopolysaccharide) and was ineffective when administered later, prior to the activation step (heat shock). CONCLUSIONS These findings suggest a novel role for the hydroxyl radical as a nonlethal intracellular signal in endothelial cell apoptosis. Moreover, the results support a role for programmed cell death in the pathogenesis of multiple organ dysfunction syndrome and suggest novel strategies for prophylaxis and therapy of the most common cause of death in surgical intensive care units.