Oxygen toxicity in mouse lung: Pathways to cell death
Oxygen toxicity in mouse lung: Pathways to cell death
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DOI：
10.1165/ajrcmb.19.4.3173
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发表时间：
1998-10-01
影响因子：
6.4
通讯作者：
Piguet, PF
中科院分区：
文献类型：
--
作者：
Barazzone, C;Horowitz, S;Piguet, PF
暴露于100%O-2的小鼠在3或4天后死亡，伴有弥漫性肺泡损伤和肺泡水肿。肺泡隔的电子显微镜下可见广泛的细胞死亡，影响内皮细胞和上皮细胞。受损细胞表现出凋亡（染色质浓缩和边集）和坏死（质膜破裂）的特征。肺DNA的电泳图谱表明，既有细胞凋亡特征的核小体间断裂，也有坏死特征的整体降解。高氧诱导p53、bax、bcl-x和Fas的RNA或蛋白质水平显著增加，已知它们在某些类型的细胞凋亡中表达。然而，我们没有检测到属于细胞凋亡“刽子手”机制的蛋白酶活性增加，如CPP 32（胱天蛋白酶3）、ICE（胱天蛋白酶1）或组织蛋白酶D。此外，ICE样蛋白酶抑制剂的施用没有显著增强对氧的抗性。此外，无论是p53缺陷型小鼠还是lpr小鼠（Fas null）都没有表现出对高氧诱导的肺损伤的抵抗力增加。这些结果表明，坏死和凋亡有助于细胞死亡期间高氧。多个凋亡途径似乎参与其中，抗凋亡策略不能减轻肺泡损伤。
Mice exposed to 100% O-2 die after 3 or 4 d with diffuse alveolar damage and alveolar edema. Extensive cell death is evident by electron microscopy in the alveolar septa, affecting both endothelial and epithelial cells. The damaged cells show features of both apoptosis (condensation and margination of chromatin) and necrosis (disruption of the plasma membrane). The electrophoretic pattern of lung DNA indicates both internucleosomal fragmentation, characteristic of apoptosis, and overall degradation, characteristic of necrosis. Hyperoxia induces a marked increase in RNA or protein levels of p53, bax, bcl-x, and Fas, which are known to be expressed in certain types of apoptosis. However, we did not detect an increased activity of proteases belonging to the apoptosis "executioner" machinery, such as CPP32 (caspase 3), ICE (caspase 1), or cathepsin D. Furthermore, administration of an ICE-like protease inhibitor did not significantly enhance the resistance to oxygen. Additionally, neither p53-deficient mice nor lpr mice (Fas null) manifested an increased resistance to hyperoxia-induced lung damage. These results show that both necrosis and apoptosis contribute to cell death during hyperoxia. Multiple apoptotic pathways seem to be involved in this, and an antiapoptotic strategy does not attenuate alveolar damage.