Li Xiang-Yun, Zhang Cheng, Wang Su-Fang, Ji Yan-Li, Wang Hua, Zhao Lei, Xu De-Xiang
Department of Toxicology, Anhui Medical University, Hefei 230032, China.
Toxicol Lett. 2008 Feb 15;176(3):169-77. doi: 10.1016/j.toxlet.2007.10.010.
Heme oxygenase-1 (HO-1) is an inducible enzyme that catalyzes the rate-limiting step in the degradation of heme to biliverdin, carbon monoxide and iron. Previous studies have demonstrated that lipopolysaccharide (LPS) upregulates the expression of HO-1 in adult mouse liver. The present study aimed to investigate the effects of maternal LPS exposure on the expression of HO-1 in fetal liver. The pregnant mice were intraperitoneally injected with different doses of LPS (1, 10, 75 microg/kg) on gestational day 17. Results showed that the expression of HO-1 in fetal liver was increased, beginning 2h after LPS, being at the highest level 24h after LPS, and remaining elevated up to 48h after LPS, whereas HO-2, the constitutive form, did not change at the various time points observed. LPS-induced upregulation of HO-1 was blocked by alpha-phenyl-N-t-butylnitrone (PBN), a free radical spin trapping agent. Correspondingly, PBN pretreatment significantly attenuated LPS-induced lipid peroxidation and glutathione (GSH) depletion in fetal liver. However, aminoguanidine (AG), a selective inhibitor of inducible nitric oxide synthase (iNOS), and pentoxifylline (PTX), an inhibitor of tumor necrosis factor alpha (TNF-alpha) synthesis, had no effect on LPS-induced upregulation of HO-1 in fetal liver. In conclusion, reactive oxygen species (ROS), rather than TNF-alpha or nitric oxide (NO), are involved in LPS-induced upregulation of HO-1 in fetal liver. These results provide new evidence that maternal LPS exposure results in oxidative stress in fetuses, which may contribute to LPS-induced developmental toxicity.
血红素加氧酶-1（HO-1）是一种诱导性酶，它催化血红素降解为胆绿素、一氧化碳和铁的限速步骤。先前的研究表明，脂多糖（LPS）可上调成年小鼠肝脏中HO-1的表达。本研究旨在探讨母体暴露于LPS对胎儿肝脏中HO-1表达的影响。在妊娠第17天，给怀孕小鼠腹腔注射不同剂量的LPS（1、10、75微克/千克）。结果显示，LPS注射后2小时，胎儿肝脏中HO-1的表达开始增加，在LPS注射后24小时达到最高水平，并在LPS注射后48小时一直保持升高，而组成型的HO-2在观察的各个时间点均未发生变化。α-苯基-N-叔丁基硝酮（PBN），一种自由基自旋捕获剂，可阻断LPS诱导的HO-1上调。相应地，PBN预处理可显著减轻LPS诱导的胎儿肝脏脂质过氧化和谷胱甘肽（GSH）耗竭。然而，诱导型一氧化氮合酶（iNOS）的选择性抑制剂氨基胍（AG）和肿瘤坏死因子α（TNF-α）合成抑制剂己酮可可碱（PTX）对LPS诱导的胎儿肝脏HO-1上调没有影响。总之，活性氧（ROS）而非TNF-α或一氧化氮（NO）参与了LPS诱导的胎儿肝脏HO-1上调。这些结果提供了新的证据，表明母体暴露于LPS会导致胎儿氧化应激，这可能导致LPS诱导的发育毒性。
