Stimulation of suicidal death of erythrocytes by rifampicin
Stimulation of suicidal death of erythrocytes by rifampicin
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DOI：
10.1016/j.tox.2012.10.006
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发表时间：
2012-12-16
期刊：
影响因子：
4.5
通讯作者：
Lang, Florian
中科院分区：
文献类型：
--
作者：
Abed, Majed;Towhid, Syeda T.;Lang, Florian
抗生素利福平被广泛用于治疗肺结核。利福平的副作用包括溶血性贫血。类似溶血性贫血的循环红细胞损失可能是由红细胞凋亡刺激引起的，红细胞凋亡是一种自杀性红细胞死亡，其特征是细胞收缩和细胞膜混乱，细胞表面暴露于磷脂酰丝氨酸（PS）。胞浆Ca ~（2+）活性（[Ca ~（2+）]（i））的增加和神经酰胺的形成是胞浆凋亡的刺激因素。本研究探讨了利福平是否以及如何引发眼睑下垂。为此，根据Fluo 3荧光、流式细胞术中前向散射的细胞体积、膜联蛋白结合的PS暴露、荧光抗体结合的神经酰胺形成和血红蛋白释放的溶血来估计[Ca 2 +]（i）。结果，暴露于利福平（>= 24 μ g/ml）48小时显著增加Fluo 3荧光、神经酰胺丰度和膜联蛋白结合，并显著降低前向散射。利福平引起轻微但显著的溶血。去除细胞外Ca 2+显着钝化，但没有完全废除利福平诱导的膜联蛋白结合。总之，人红细胞暴露于利福平后会发生自杀性红细胞死亡或红细胞凋亡，这种效应至少部分是由于胞浆Ca 2+浓度增加和刺激神经酰胺形成所致。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
The antibiotic rifampicin is widely used in the treatment of tuberculosis. Side effects of rifampicin include hemolytic anemia. Loss of circulating erythrocytes resembling hemolytic anemia could result from stimulation of eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) exposure at the cell surface. Stimulators of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+](i)) and formation of ceramide. The present study explored, whether and, if so, how rifampicin triggers eryptosis. To this end, [Ca2+](i) was estimated from Fluo3 fluorescence, cell volume from forward scatter in flow cytometry, PS exposure from annexin binding, ceramide formation from binding of fluorescent antibodies and hemolysis from hemoglobin release. As a result, a 48 h exposure to rifampicin (>= 24 mu g/ml) significantly increased Fluo3 fluorescence, ceramide abundance and annexin binding, and significantly decreased forward scatter. Rifampicin triggered slight, but significant hemolysis. Removal of extracellular Ca2+ significantly blunted, but did not fully abolish rifampicin induced annexin binding. In conclusion, exposure of human erythrocytes to rifampicin is followed by suicidal erythrocyte death or eryptosis, an effect at least partially due to increase of cytosolic Ca2+ concentration and stimulation of ceramide formation. (C) 2012 Elsevier Ireland Ltd. All rights reserved.