Esomeprazole counteracts chlorine toxicity in pregnant animals

我们已经证明，怀孕的小鼠特别容易受到BR2暴露和发育的伤害 使人联想到先兆子痫的症状。我们鉴定了一种短剪接变种的胎盘产生 FMS样酪氨酸激酶1(sFlt-1)及其对血管内皮生长因子信号转导的抑制作用 (血管内皮生长因子)作为一种潜在机制。此外，使用V型磷酸二酯酶抑制剂治疗 (PDE5i)他达拉非或重组血管内皮生长因子治疗通过降低血液减少妊娠特异性BR2毒性 降低血压，恢复心脏功能，减少呼吸系统和代谢性酸中毒，减少肺水肿。在……里面 初步数据表明，Cl2暴露对怀孕小鼠具有高度毒性，导致严重的母体 体重减轻，孕产妇死亡率高，胎儿生长受限严重。更多初步数据显示 用质子泵抑制剂(PPI)埃索美拉唑(ESO；每天30 mg/kg灌胃)治疗，这是 Nexium®的活性成分可改善接触Cl2的孕妇的体重增加和胎儿生长 老鼠。ESO是一种PPI，但被发现能刺激核因子(红系衍生2)样2(Nrf2)，导致 包括HO-1在内的抗氧化基因的表达也增加了。HO-1对HO的发展和 维持正常妊娠。HO-1表达的刺激已被证明具有拮抗机制 在动物模型中可引起子痫前期并改善先兆子痫的诊断体征。我们的具体目标 旨在检验ESO(每天30 mg/kg灌胃)通过以下方式提高存活率和胎儿生长的假设 通过激活核因子(红系衍生的2)样2(NRF2)诱导HO-1，其保护作用将是 伴随着接触Cl2的怀孕小鼠出现的介体减少和先兆子痫症状。 为了测试这些建议的机制，我们将比较ESO和FDA批准的另一种NRF2的有效性 激活剂富马酸二甲酯(DMF；Tecfidera®)，我们将评估Nrf2的化学抑制剂的效果 (ML385)和HO-1(锡原卟啉IX；SnPP)对ESO疗效的影响。SA#1：比较以下各项的疗效 ESO(30 mg/kg/d灌胃)与DMF(100 mg/kg/d/d灌胃)降低孕产妇死亡率、胎儿 Cl2暴露孕鼠的生长受限和先兆子痫症状。DMF是FDA批准的 治疗多发性硬化症的药物。与ESO相似，已知DMF可以激活Nrf2，但它不是质子 泵抑制剂。将股票期权和DMF的效率进行比较，可以分离出 NRF2的激活来自于ESO的PPI功能。SA#2来测试Nrf2激活和HO-2的机制作用 1 ESO对Cl2暴露毒性的保护作用。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 用于测试ESO和/或DMF对两者的剂量依赖效应的全面应用(UO1)的基础 Cl2和Br2诱导的妊娠小鼠的病理，包括连续监测血压 遥测，以及使用Nrf2和HO-1基因靶向的小鼠模型进行的其他机制研究。

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.