Hypoxia protects human lung microvascular endothelial and epithelial-like cells against oxygen toxicity - Role of phosphatidylinositol 3-kinase
Hypoxia protects human lung microvascular endothelial and epithelial-like cells against oxygen toxicity - Role of phosphatidylinositol 3-kinase
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DOI：
10.1165/rcmb.2002-0004oc
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发表时间：
2003-02-01
影响因子：
6.4
通讯作者：
White, CW
中科院分区：
文献类型：
--
作者：
Ahmad, S;Ahmad, A;White, CW
低氧预处理可以保护心脏等多种器官免受氧化相关损伤。我们之前表明，暴露于缺氧的大鼠也表现出对致命性肺氧毒性的抵抗力。其基本机制以及类似的预处理是否适用于细胞模型尚不清楚。在本研究中，发现低氧预暴露对人肺微血管内皮细胞（HLMVEC）和II型上皮样A549细胞中高氧诱导的细胞死亡具有显着的保护作用。这种缺氧效应是由磷脂酰肌醇 3-激酶 (P13-K) 信号通路介导的，因为在预暴露于缺氧期间，P13-K 抑制剂 LY294002 和渥曼青霉素的存在完全阻断了随后的保护。此外，还发现缺氧依赖性的高氧保护与缺氧时 P13-K 活性增加 2 倍有关。与空载体对照相比，催化活性 IA 类 P13-K p110α 亚型的瞬时过表达也使 A549 细胞的存活率提高了 2 倍。这些结果表明，缺氧诱导的 P13-K 激活是获得对随后的高氧毒性的抵抗力的重要事件。
Hypoxic preconditioning is protective against oxidant-related damage in various organs, such as the heart. We previously showed that rats exposed to hypoxia also exhibit resistance to lethal pulmonary oxygen toxicity. The underlying mechanism and whether similar preconditioning is applicable to cellular models is unknown. In the present study, it was found that hypoxic pre-exposure induces a significant protective effect against hyperoxia-induced cell death in human lung microvascular endothelial cells (HLMVECs) and epithelial type II-like A549 cells. This effect of hypoxia is mediated by the phosphatidylinositol 3-kinase (P13-K) signaling pathway because the presence of the P13-K inhibitors, LY294002 and wortmannin, during pre-exposure to hypoxia completely blocks subsequent protection. Further, the hypoxia-dependent protection from hyperoxia was found to be associated with a 2-fold increase in P13-K activity in hypoxia. Transient overexpression of a catalytically active class IA P13-K p110alpha isoform also enhanced survival of A549 cells 2-fold compared with the empty vector control. These results indicate that hypoxia-induced activation of P13-K is an important event in the acquisition of resistance against subsequent hyperoxic toxicity.