Superoxide dismutase protects against apoptosis and alveolar enlargement induced by ceramide
Superoxide dismutase protects against apoptosis and alveolar enlargement induced by ceramide
复制标题
DOI：
10.1152/ajplung.00448.2007
复制
发表时间：
2008-07-01
影响因子：
4.9
通讯作者：
Tuder, Rubin M.
中科院分区：
文献类型：
--
作者：
Petrache, Irina;Medler, Terry R.;Tuder, Rubin M.
导致肺气肿发生的分子事件包括氧化应激的产生和肺泡细胞凋亡。氧化应激上调神经酰胺，促凋亡信号鞘脂，引发进一步的氧化应激和肺泡空间扩大，如VEGF阻断肺气肿的实验模型所示。由于肺泡细胞凋亡和氧化应激相互作用介导肺泡破坏，我们假设神经酰胺产生的氧化应激是其对肺泡的致病作用所必需的。为了模拟神经酰胺对肺的直接作用，小鼠气管内注射神经酰胺(Cer（12:0）或Cer(8:0)；1 mg/kg)或车辆。一般caspase抑制剂可抑制细胞凋亡。神经酰胺的增加模拟了人类肺气肿肺中发现的水平，增加了氧化应激，并在48小时内降低了肺超氧化物歧化酶活性（独立于caspase激活）。与野生型小鼠相比，过度表达人类Cu/Zn SOD的转基因小鼠明显免受神经酰胺诱导的超氧化物产生、细胞凋亡和空气空间扩大的影响。在Cu/Zn SOD转基因小鼠中，神经酰胺处理后肺酸性鞘磷脂酶的激活被消除。由于香烟烟雾诱导的小鼠肺气肿同样可以通过Cu/Zn SOD过表达得到改善，我们假设香烟烟雾可能会诱导小鼠肺中的神经酰胺。利用串联质谱法，我们记录了暴露于香烟烟雾4周的成年小鼠肺神经酰胺的增加。综上所述，神经酰胺诱导的肺超氧化物积累可能是神经酰胺促进肺细胞凋亡作用的关键步骤。这项工作暗示过量的肺神经酰胺通过氧化还原依赖机制作为肺损伤的放大器。
The molecular events leading to emphysema development include generation of oxidative stress and alveolar cell apoptosis. Oxidative stress upregulates ceramides, proapoptotic signaling sphingolipids that trigger further oxidative stress and alveolar space enlargement, as shown in an experimental model of emphysema due to VEGF blockade. As alveolar cell apoptosis and oxidative stress mutually interact to mediate alveolar destruction, we hypothesized that the oxidative stress generated by ceramide is required for its pathogenic effect on lung alveoli. To model the direct lung effects of ceramide, mice received ceramide intratracheally (Cer(12:0) or Cer(8:0); 1 mg/kg) or vehicle. Apoptosis was inhibited with a general caspase inhibitor. Ceramide augmentation shown to mimic levels found in human emphysema lungs increased oxidative stress, and decreased, independently of caspase activation, the lung superoxide dismutase activity at 48 h. In contrast to their wild-type littermates, transgenic mice overexpressing human Cu/Zn SOD were significantly protected from ceramide-induced superoxide production, apoptosis, and air space enlargement. Activation of lung acid sphingomyelinase in response to ceramide treatment was abolished in the Cu/Zn SOD transgenic mice. Since cigarette smoke-induced emphysema in mice is similarly ameliorated by the Cu/Zn SOD overexpression, we hypothesized that cigarette smoke may induce ceramides in the mouse lung. Utilizing tandem mass spectrometry, we documented increased lung ceramides in adult mice exposed to cigarette smoke for 4 wk. In conclusion, ceramide-induced superoxide accumulation in the lung may be a critical step in ceramide's proapoptotic effect in the lung. This work implicates excessive lung ceramides as amplifiers of lung injury through redox-dependent mechanisms.