Melatonin alleviates lipopolysaccharide‐induced placental cellular stress response in mice
Melatonin alleviates lipopolysaccharide‐induced placental cellular stress response in mice
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DOI：
10.1111/j.1600-079x.2011.00860.x
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发表时间：
2011-05
影响因子：
10.3
通讯作者：
Hua Wang;Ling Li;Mei Zhao;Yuan-Hua Chen;Zhihui Zhang;Cheng Zhang;Yan-Li Ji;Xiu-hong Meng
中科院分区：
文献类型：
--
作者：
Hua Wang;Ling Li;Mei Zhao;Yuan-Hua Chen;Zhihui Zhang;Cheng Zhang;Yan-Li Ji;Xiu-hong Meng
摘要：褪黑素对脂多糖(LPS)诱导的小鼠胎儿死亡和宫内生长迟缓有保护作用。然而，其分子机制仍不清楚。在本研究中，我们研究了褪黑素对内毒素诱导的胎盘细胞应激的影响。孕鼠在内毒素(300μg/kg，ip)前30min和后150min分别给予褪黑素(5.0 mg/kg，ip)。于妊娠第15天检测胎盘氧化应激、内质网应激、低氧应激、热应激。正如预期的那样，母体注射脂多糖导致胎盘谷胱甘肽(GSH)耗竭，并上调胎盘抗氧化酶的表达。此外，内毒素还可显著增加胎盘组织诱导型一氧化氮合酶(INOS)水平，增强胎盘3-硝基酪氨酸残基的强度。注射脂多糖的孕鼠胎盘出现内质网应激，表现为GRP78表达降低，eIF2α和JNK明显磷酸化，CHOP表达增加。此外，低氧应激标志物胎盘组织中缺氧诱导因子-1α、血管内皮生长因子和内毒素-1的表达水平显著升高。热应激的标志物--血红素加氧酶(HO)-1也在脂多糖处理的孕鼠胎盘中上调。有趣的是，服用褪黑激素后，妊娠小鼠的胎盘氧化应激、低氧应激和内质网应激显著减轻，而褪黑素对脂多糖诱导的胎盘HO-1表达几乎没有影响。总而言之，母亲服用褪黑素可以减轻胎盘中由内毒素引起的细胞压力。褪黑素可能是有用的药理药物，以保护胎儿免受内毒素引起的宫内死亡和宫内生长受限。
Abstract: Melatonin protects mice from lipopolysaccharide (LPS)‐induced fetal death and intra‐uterine growth retardation. Nevertheless, its molecular mechanism remains obscure. In the present study, we investigated the effects of melatonin on LPS‐induced cellular stress in placenta. Pregnant mice were given with melatonin [5.0 mg/kg, intraperitoneal (i.p.)] 30 min before and 150 min after LPS (300 μg/kg, i.p.) on gestational day 15. Oxidative stress, endoplasmic reticulum (ER) stress, hypoxic stress, and heat stress in placenta were analyzed at 4 hr after LPS. As expected, maternal LPS administration resulted in placental glutathione (GSH) depletion and up‐regulated the expression of placental antioxidative enzymes. In addition, LPS significantly increased the level of inducible nitric oxide synthase (iNOS) and enhanced the intensity of placental 3‐nitrotyrosine residues. An ER stress, as determined by a decreased GRP78 expression, an obvious eIF2α and JNK phosphorylation, and an increased CHOP expression, were observed in placenta of pregnant mice injected with LPS. In addition, LPS significantly increased mRNA level of placental HIF‐1α, VEGF, and ET‐1, the markers of hypoxic stress. Heme oxygenase (HO)‐1, a marker of heat stress, was also up‐regulated in placenta of LPS‐treated pregnant mice. Interestingly, LPS‐induced placental oxidative stress, hypoxic stress, and ER stress were significantly alleviated when pregnant mice were given with melatonin, whereas melatonin had little effect on LPS‐evoked placental HO‐1 expression. In conclusion, maternally administered melatonin alleviates LPS‐induced cellular stress in the placenta. Melatonin may be useful as pharmacological agents to protect the fetuses against LPS‐induced intra‐uterine fetal death and intra‐uterine growth restriction.