Esomeprazole counteracts chlorine toxicity in pregnant animals

我们已经表明，怀孕的小鼠特别容易受到Br2暴露造成的伤害，并发展为 先兆子痫的症状我们发现胎盘产生的短剪接变异体， FMS样酪氨酸激酶1（sFLT-1）和随后通过血管内皮生长因子抑制信号传导 （VEGF）作为潜在机制。此外，用V型磷酸二酯酶抑制剂治疗 （PDE5i）他达拉非或重组VEGF治疗通过减少血液中Br2的浓度来减轻妊娠特异性Br2毒性 这类药物可降低血压、恢复心脏功能、减少呼吸和代谢性酸中毒以及减少肺水肿。在 初步数据，我们表明，氯暴露是高度有毒的怀孕小鼠，导致严重的孕产妇 体重减轻、产妇死亡率高和胎儿生长严重受限。其他初步数据显示， 用质子泵抑制剂（PPI）埃索美拉唑（ESO; 30 mg/kg/天，灌胃）治疗， Nexium®的活性成分，可改善暴露于Cl2的孕妇的母体体重增加和胎儿生长 小鼠ESO是一种PPI，但被发现刺激核因子（红细胞衍生2）样2（Nrf2），导致 增加抗氧化基因的表达，包括HO-1。HO-1对发展至关重要， 维持正常妊娠。刺激HO-1表达已显示出拮抗机制 其在动物模型中引起先兆子痫并改善先兆子痫的诊断体征。我们的具体目标 旨在检验ESO（30 mg/kg/天，灌胃）通过以下方式改善存活率和胎仔生长的假设： 通过激活核因子（红细胞衍生2）样2（Nrf2）诱导HO-1， 伴随着减少的介质和先兆子痫的症状发生在Cl2暴露的怀孕小鼠。 为了测试这些提出的机制，我们将比较ESO与另一种FDA批准的Nrf2的疗效。 激活剂富马酸二甲酯（DMF; Tecfidera®），我们将评估Nrf2化学抑制剂的作用 （ML385）和HO-1（锡原卟啉IX; SnPP）对ESO功效的影响。SA #1：比较以下药物的疗效 ESO（30 mg/kg/天，灌胃）与DMF（100 mg/kg/天，灌胃）联合给药，以降低母体死亡率、胎仔死亡率 在暴露于Cl 2的怀孕小鼠中的生长限制和先兆子痫症状。DMF是FDA批准的 治疗多发性硬化症的药物。与ESO类似，已知DMF可激活Nrf2，但它不是质子 泵抑制剂。比较ESO与DMF的功效将允许分离以下因素的机制贡献： Nrf2激活来自ESO的PPI功能。SA#2为了测试Nrf2激活和HO-1的机制作用， 1. ESO对Cl 2暴露毒性的保护活性。我们将使用Nrf2的小分子抑制剂 （ML385）和HO-1（锡原卟啉IX; SnPP）用于机械测试。这项研究计划的成功将是 用于检测ESO和/或DMF对两种药物的剂量依赖性疗效的完整申请（UO 1）的基础 Cl2和Br2在妊娠小鼠中诱导的病理学，包括用 遥测和使用Nrf2和HO-1基因靶向的鼠模型的另外的机制研究。

We have shown that pregnant mice are particularly susceptible to injury caused by Br2 exposure and develop symptoms that are reminiscent of preeclampsia. We identified placental production of a short splice variant of FMS-like tyrosine kinase 1 (sFLT-1) and consequent inhibition of signaling via vascular endothelial growth factor (VEGF) as an underlying mechanism. Additionally, treatment with the type V phosphodiesterase inhibitor (PDE5i) tadalafil or treatment with recombinant VEGF mitigate pregnancy-specific Br2 toxicty by reducing blood pressure, restoring heart function, reducing respiratory and metabolic acidosis and reducing lung edema. In preliminary data, we demonstrate that Cl2 exposure is highly toxic to pregnant mice, resulting in severe maternal weight loss, high rate of maternal mortality and severe fetal growth restriction. Additional preliminary data show that treatment with the proton pump inhibitor (PPI) esomeprazole (ESO; 30 mg/kg/day by gavage), which is the active ingredient of Nexium®, results in improved maternal weight gain and fetal growth in Cl2 exposed pregnant mice. ESO is a PPI, but was found to stimulate nuclear factor (erythroid-derived 2)–like 2 (Nrf2), resulting in the increased expression of antioxidant genes including HO-1 as well. HO-1 is critical for the development and maintenance of normal pregnancy. Stimulation of HO-1 expression has been shown to antagonize mechanisms that cause preeclampsia and ameliorate diagnostic signs of preeclampsia in animal models. Our specific aims were designed to test the hypothesis that ESO (30 mg/kg/day by gavage) improves survival and fetal growth by inducing HO-1 via activation of nuclear factor (erythroid-derived 2)–like 2 (Nrf2) and the protective effects will be accompanied by reduced mediators and symptoms of preeclampsia that occur in Cl2 exposed pregnant mice. To test these proposed mechanisms, we will compare the efficacy of ESO to another, FDA-approved Nrf2 activator dimethyl fumarate (DMF; Tecfidera®) and we will assess the effects of the chemical inhibitors of Nrf2 (ML385) and HO-1 (tin proto porphyrin IX; SnPP) on the efficacy of ESO. SA#1: To compare the efficacy of ESO (30 mg/kg/day by gavage) with DMF (100 mg/kg/day by gavage) to reduce maternal mortality, fetal growth restriction and symptoms of preeclampsia in Cl2 exposed pregnant mice. DMF is an FDA approved drug for the treatment of multiple sclerosis. Similar to ESO, DMF is known to activate Nrf2, but it is not a proton pump inhibitor. Comparing the efficacy of ESO to DMF will allow to dissociate the mechanistic contribution of Nrf2 activation from the PPI function of ESO. SA#2 To test the mechanistic roles of Nrf2 activation and HO- 1 activity in protection from Cl2 exposure toxicity by ESO. We will use the small molecule inhibitors of Nrf2 (ML385) and HO-1 (tin protoporphyrin IX; SnPP) for mechanistic testing. Success of this research plan will be the basis of a full application (UO1) for the testing of dose-dependent efficacy of ESO and/or DMF against both Cl2 and Br2 induced pathology in pregnant mice, including the continuous monitoring of blood pressure with telemetry, and additional mechanistic studies using Nrf2 and HO-1 gene-targeted murine models.