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

卤溴（Br 2）用作水消毒剂，用于漂白纤维，用于制造抗癫痫药 药物、染料、阻燃剂、杀虫剂、钻井液和汽油添加剂。吸入后会导致 呼吸水平依赖性急性和慢性肺和全身损伤， 气道刺激，对心肺系统和其他器官造成重大损害，可导致死亡。 存活者可能发展为反应性气道疾病综合征、肺纤维化以及限制性和 阻塞性肺疾病目前，没有研究评估Br 2的急性和慢性后遗症 尽管美国人口普查局的数据预测， 在美国，每100人中就有一人怀孕。妊娠小鼠在妊娠第15天（E15）暴露于Br 2（600 ppm，持续30分钟）在四天内导致75%的死亡率，相比之下，男性或非妊娠者的死亡率为25%。 女性（p<0.001）。当在E19分娩时，暴露于Br 2的存活小鼠的胎儿表现出严重的胎儿生长 限制（FGR）和胎儿死亡（FD）。胎盘发育不良， 短FMS样酪氨酸激酶-1（sFlt-1），一种抗血管生成介质和先兆子痫和 肺动脉高压当自然出生时，没有一个胎儿存活下来。口服给药FDA- 批准的5型环核苷酸特异性磷酸二酯酶抑制剂（PDE 5i;他达拉非）给药后， 暴露，显着改善产妇生存，胎儿生长限制和新生儿存活。我们 假设溴化中间体，由Br 2和HOBr与缩醛磷脂反应形成， 损伤内皮和胎盘，诱导血管收缩剂和抗血管生成剂的释放 介导肺血管收缩、肺动脉压升高和右心室收缩的介质 心室功能障碍他达拉非恢复肺和子宫血管舒张，保护心脏功能， 改善子宫/胎盘血液供应，从而使母体和胎儿存活。我们将测试这些建议 我们将进行必要的疗效研究，以确定最佳的治疗方案， 他达拉非可降低母体发病率和死亡率，改善胎儿生长受限，增加胎儿 暴露后口服给药时的存活率。具体目标#1。为了验证暴露于 妊娠小鼠在E15时暴露于Br 2会引起广泛的肺损伤以及全身性内皮损伤、胎盘损伤、 损伤、肺动脉高压、右心衰竭导致产妇死亡、胎儿生长受限， 胎儿死亡/死产。具体目标#2：确定与艾滋病毒/艾滋病有关的事件顺序和机制。 发生母体血管收缩、肺动脉高压和右心衰竭。具体目标#3到 研究卤素暴露后他达拉非给药降低母体和胎儿死亡率的有效性 死亡和发病率，并开发妊娠期Br 2毒性的家兔（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.