NEW PRENATAL THERAPY FOR CONGENITAL DIAPHRAGMATIC HERNIA

CDH的情况发生在隔肌分离时 胸部从腹部，在发育中完全下落形成。 胎儿。肠道不再局限于腹部，而是突出到 胸腔。这种缺陷通常与肺的不成熟有关； 这并不是一种罕见的疾病，几乎每2000例孕妇中就有一例受到影响。 尽管在婴儿手术和重症监护方面取得了许多重大进展 对于CDH，畸形的死亡率仍然高达60%。这个 婴儿死于肺功能不足，这是1) 肺发育不良和2)持续性肺动脉高压 刚出生的。足月儿CDH的肺与正常足月新生儿的肺相似。 早产儿。我们使用了硝苯醚诱导的CDH模型。 通过生化手段证明肺未成熟的胎鼠， 形态计量学、生理学和分子生物学标准。我们已经展示了 此外，足月CDH大鼠的致死性未成熟肺可以 通过对母亲进行剂量的胃肠外糖皮质激素治疗而改善 从目前用于加速肺发育的疗法推断出来的 早产的人类婴儿。添加甲状腺激素会增加这一点 效果。我们将寻找更有效的肺生长促进剂 基因水平，评估发育调节基因在CDH中的表达， 并探讨细胞凋亡在CDH中的作用。我们已经开发出了一种智能 硝苯醚致肺发育不良的体外器官培养体系 用于筛选新制剂的定量数学和分形技术；我们 将在大鼠模型中测试它们的有效性并优化剂量，然后扩展 这些实验针对的是胚胎绵羊，在其中进行了CDH手术 而不是药理上创造出来的。这些系统的组合将允许 美国将预先试验和开发可用于治疗CDH的适当疗法 在未来对患有CDH的人类进行产前治疗的临床试验中 在子宫中被超声波检测到。

The condition of CDH occurs when the diaphragmatic muscle, which separates the chest from the abdomen, falls to form completely in the developing fetus. The intestines, no longer confined to the abdomen, herniate into the thorax. The defect is often associated with immaturity of the lungs; it is not a rare condition, affecting nearly one in 2,000 pregnancies. Despite many major advances in the surgery and intensive care of infants with CDH, the mortality from the malformation remains as high as 60%. The infants die from inadequate lung function, which is a combination of 1) pulmonary hypoplasia and 2) persistent pulmonary hypertension of the newborn. Lungs of full term infants with CDH are similar to lungs of premature infants. We have used the nitrofen-induced model of CDH in the fetal rat to demonstrate that the lungs are immature by biochemical, morphometric, physiologic, and molecular biologic criteria. We have shown further that the lethally immature lungs of the full term CDH rats can be improved by treating the mothers with parenteral glucocorticoids at doses extrapolated from the current therapy used to accelerate lung development of premature human babies. Addition of thyroid hormone augments this effect. We will search for more potent pulmonary growth enhancers at the gene level, evaluate expression of developmentally regulated genes in CDH, and investigate the role of apoptosis in CDH. We have developed an in vitro organ culture system of nitrofen-induced pulmonary hypoplasia using quantitative mathematical and fractal techniques to screen new agents; we will test their efficacy and optimize dosing in the rat model, then extend these experiments to fetal sheep in whom CDH has been surgically, rather than pharmacologically, created. Combination of these systems will allow us to pretest and develop appropriate therapies for CDH that can be used in future clinical trials for prenatal treatment of humans in whom CDH has been detected in utero by ultrasound.