Hyperoxia and apoptosis. Too much of a good thing?
Hyperoxia and apoptosis. Too much of a good thing?
复制标题
高氧和细胞凋亡。
DOI：
10.1164/rccm.201010-1756ed
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发表时间：
2011
影响因子：
24.7
通讯作者：
Schmidt,EricP
中科院分区：
文献类型：
--
作者：
Tuder,RubinM;Hunt,JamesM;Schmidt,EricP
24小时内使用的氧气量接近200加仑。供应气体的经销商对所需的量感到惊讶，而且，想为我服务，给我发了一条警告信息，暗示没有人可能忍受如此大量的氧气，因为对系统的刺激和组织燃烧的危险程度增加。(1)In自Blodgett博士首次报道使用持续供氧治疗肺炎以来的120年（1），氧气已成为医学上最常用的处方药之一。作为一种“药理学药物”，氧气具有公认的临床适应症（例如，持续性皮肤感染、中风、肺部疾病），但治疗窗口不太为人所知，过量常压或高压补充可能会产生毒性（2）。与适应低氧血症的进化压力相反，缺乏针对高氧的自然选择可能使哺乳动物无法科普这些毒性（3）。因此，向动物给予高水平的氧气会产生显著的肺毒性，其特征在于急性肺损伤（ALI）典型的明确定义的渗出和增殖阶段（4）。虽然高氧肺损伤以肺泡细胞凋亡和坏死为特征（5），但尚不清楚这些细胞死亡过程如何与炎症联合收割机结合以产生肺表型，最明显的是与其他过程（包括败血症、创伤和输血等）引起的ALI相关（4）。在本期杂志中，Budinger和他的同事（pp. 1043-1054）结合了最先进的方法和遗传修饰的小鼠模型，以解决细胞凋亡、细胞凋亡调节分子信号和氧化应激在高氧ALI发展中的潜在作用（6）。使用的综合方法允许作者重新访问以前发表的数据，同时增加了关于高氧如何损害肺的大量新见解。尽管关于高氧介导的肺损伤的发病机制的实验数据越来越多，但细胞凋亡是否是高氧毒性的中心特征并因此是有价值的治疗靶点，或者相反，是肺的几种细胞和生化损伤积累的基础的终末事件，仍然没有解决。众所周知，高氧通过氧化应激引发肺细胞损伤。以前的研究表明，高氧通过线粒体和线粒体膜增加氧化剂的产生，
The amount of [oxygen] employed was not far from two hundred gallons in twenty-four hours. The dealer who supplied the gas was astonished at the amount required, and, thinking to do me a service, sent me a cautionary message, implying that no human being could possibly stand so great an amount of oxygen, on account of the dangerous degree of stimulation to the system and the increased combustion of tissue.(1)In the 120 years since Dr. Blodgett first reported the use of continuous oxygen in the management of pneumonia (1), oxygen has become one of the most commonly prescribed drugs in medicine. As a ‘‘pharmacologic drug,’’oxygen has well-recognized clinical indications (eg, persistent cutaneous infection, stroke, pulmonary disease) but a less well-recognized therapeutic window, with potential toxicities arising from excessive normobaric or hyberbaric supplementation (2). In contrast to the evolutionary pressure to adapt to hypoxemia, the lack of natural selection against hyperoxia may have rendered mammals ill-equipped to cope with these toxicities (3). Consequently, the administration of high levels of oxygen to animals produces significant pulmonary toxicity, characterized by well-defined exudative and proliferative stages typical for acute lung injury (ALI)(4). While hyperoxic lung injury is notable for alveolar cell apoptosis and necrosis (5), it is unclear how these processes of cell death combine with inflammation to produce the lung phenotypes, most notably in relation to ALI caused by other processes, including sepsis, trauma, and blood transfusion, among others (4). In this issue of the Journal, Budinger and colleagues (pp. 1043–1054) incorporate state-of-the-art methodology and genetically modified mouse models to address the potential role of apoptosis, apoptosis-regulating molecular signals, and oxidative stress in the development of hyperoxic ALI (6). The integrated approach used allowed the authors to revisit previously published data, while adding considerable novel insights on how hyperoxia may damage the lung. Despite a growing body of experimental data regarding the pathogenesis of hyperoxia-mediated lung injury, it remains unsolved whether apoptosis is the central feature of hyperoxia toxicity and therefore a worthy therapeutic target or, conversely, is a terminal event underlying the accumulation of several cellular and biochemical injuries to the lung. It is well recognized that hyperoxia triggers lung cell injury via oxidative stress. Previous investigations have indicated that hyperoxia increases oxidant generation through mitochondrial and