CIALIS® reverses halogen induced injury to pregnant animals and their offspring

卤素溴(Br2)用作水消毒剂，用于漂白纤维，用于制造抗癫痫药 药品、染料、阻燃剂、杀虫剂、钻井液和汽油添加剂。吸入后，它会引起 暴露水平依赖的急性和慢性肺和全身损伤，范围从轻微的眼睛和 呼吸道刺激，对心肺系统和其他器官造成严重损害，可导致死亡。 幸存者可能会发展为反应性呼吸道疾病综合征、肺纤维化以及限制性和 阻塞性肺病。目前，还没有评估BR2的急性和慢性后遗症的研究 在怀孕的啮齿动物和非啮齿动物模型中吸入，尽管美国人口普查局的数据预测有两种 在美国，每100个人中就有一个怀孕。妊娠15天(E15)孕鼠暴露于BR2(600) Ppm，30分钟。)结果在四天内死亡率为75%，而男性或未怀孕的死亡率为25% 女性(P&lt；0001)。当在E19出生时，暴露于BR2的存活小鼠的胚胎表现出严重的胎儿生长 限制妊娠(FGR)和胎儿死亡(FD)。胎盘发育不良，表达水平升高的 短FMS样酪氨酸激酶-1(sFlt-1)是子痫前期和子痫前期的抗血管生成介质和生物标志物 肺动脉高压。当自然出生时，没有一个胎儿存活下来。口服FDA- 批准的5型环核苷酸特异性磷酸二酯酶抑制剂(PDE5I；他达拉非)用于大坝- 暴露，极大地改善了产妇存活率、胎儿生长受限和新生儿存活率。我们 假设由Br2和HOBr2与血浆原反应形成的溴化中间体 损伤血管内皮细胞和胎盘，导致血管收缩因子释放和抗血管生成 这些介质依次介导肺血管收缩、肺动脉压升高和右 心功能不全。他达拉非恢复肺和子宫血管扩张，保护心脏功能和 改善子宫/胎盘的血液供应，从而提高产妇和胎儿的存活率。我们将对这些建议进行测试 我们将进行必要的疗效研究，以确定最佳的治疗方案 他达拉非降低孕产妇发病率和死亡率，改善胎儿生长受限，增加胎儿 暴露后口服给药可存活。具体目标#1.检验暴露于 妊娠15天感染BR2的小鼠会引起广泛的肺损伤和全身内皮细胞损伤，胎盘 伤害、肺动脉高压、导致孕产妇死亡的右心衰竭、胎儿生长受限和 胎儿死亡/死产。具体目标2：确定事件的顺序和涉及的机制 母体血管收缩、肺动脉高压和右心衰竭的发展。具体目标3.至 卤素暴露后应用他达拉非降低母婴死亡率的效果观察 死亡率和发病率，并建立怀孕期间BR2毒性的兔(非啮齿动物)模型。

The halogen bromine (Br2) is used as water disinfectant, for bleaching fibers, for manufacturing antiepileptic drugs, dyestuffs, flame-retardants, insecticides, drilling fluids, and gasoline additives. When inhaled, it causes exposure-level-dependent acute and chronic pulmonary and systemic injuries ranging from mild eye and airway irritation, to significant damage to cardiopulmonary system and other organs, which can lead to death. Survivors may develop reactive airway disease syndrome, pulmonary fibrosis as well as restrictive and obstructive pulmonary diseases. Presently, there are no studies evaluating acute and chronic sequelae of Br2 inhalation in pregnant rodent and non-rodent models, even though US census bureau data predicts two of every 100 people in the US being pregnant. Exposure of pregnant mice at gestational day 15 (E15) to Br2 (600 ppm for 30 min.) results in 75% mortality over four days, in contrast to 25% mortality in males or non-pregnant females (p<0001). When delivered at E19, fetuses of surviving Br2-exposed mice exhibit severe fetal growth restriction (FGR) and fetal demise (FD). Placentas are poorly developed and express increased levels of short-FMS-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic mediator and biomarker of both preeclampsia and pulmonary hypertension. When born naturally, none of the fetuses survive. Oral administration of an FDA- approved type 5 cyclic nucleotide-specific phosphodiesterase inhibitor (PDE5i; tadalafil) to the dams post- exposure, dramatically improved maternal survival, fetal growth restriction and neonatal survival. We hypothesize that brominated intermediates, formed by the reaction of Br2 and HOBr with plasmalogens cause injury to the endothelium and the placenta, inducing the release of vasoconstrictor and anti-angiogenic mediators which in turn mediate pulmonary vasoconstriction, increased pulmonary artery pressure and right ventricular dysfunction. Tadalafil restores pulmonary and uterine vasodilation, preserves heart function and improves uterine/placental blood supply resulting in maternal and fetal survival. We will test these proposed mechanisms and we will perform the necessary efficacy studies to identify the optimum therapeutic regimen of tadalafil to decrease maternal morbidity and mortality, improve fetal growth restriction and increase fetal survival when administered orally post exposure. Specific Aim #1. To test the hypothesis that exposure of pregnant mice to Br2 at E15 causes extensive pulmonary injury as well as systemic endothelial injury, placental injury, pulmonary hypertension, right heart failure resulting in maternal mortality, fetal growth restriction and fetal demise/stillbirth. Specific Aim #2: To identify the sequence of events and mechanisms involved in the development of maternal vasoconstriction, pulmonary hypertension and right heart failure. Specific Aim #3. To investigate the efficacy of post halogen exposure administration of tadalafil to decrease maternal and fetal death and morbidity and to develop a rabbit (non-rodent) model of Br2 toxicity in pregnancy.