Pilot Study of an Inhaled Treatment for Bronchopulmonary Dysplasia

摘要/总结： 支气管肺发育不良（BPD）是早产儿存活者的一种慢性心肺并发症， 出生，美国每年有超过10，000例新诊断，医疗保健费用估计超过 二十五亿美元在我的NHLBI K 08期间，我已经证明了S- 亚硝基硫醇分解代谢酶，S-亚硝基谷胱甘肽还原酶（GSNO还原酶），阻止 高氧鼠BPD的所有方面，包括肺血管特征。此外，增加气道 GSNO逆转BPD气道高反应性并促进这些小鼠的支气管扩张。GSNO- 补充剂，吸入亚硝酸乙酯，已被安全和成功地用于治疗肺动脉高压， 机械通气的人类新生儿在这里，我提出了一个试点研究，使用吸入亚硝酸乙酯治疗 患有BPD婴儿缺氧性呼吸衰竭与吸入的一氧化氮（iNO）不同，亚硝酸乙酯迅速， 在动物模型中显著增加肺GSNO水平，并应有助于逆转支气管痉挛 和通气/灌注不匹配的特征。我相信这项初步研究将是一项特别重要的研究， 我的K 08数据的有价值的临床应用，因为其他呼吸衰竭的新治疗方法还没有被 用于治疗BPD患者的呼吸衰竭 作为我们的主要临床结果变量，我们将有把握度（>0.9）检测到41%（+ 27）的改善， 吸入亚硝酸乙酯治疗4小时前后的氧饱和指数。我们的新生儿重症监护室忙碌 彩虹婴儿和儿童医院，每年有超过25名婴儿患有BPD，符合此条件 两年飞行员我们也很幸运，校园里有熟悉亚硝酸乙酯在人类中使用的调查人员， Drs.詹姆斯·雷诺兹和乔纳森·斯塔姆勒值得注意的是，斯塔姆勒博士是最初的首席调查员， 新生儿亚硝酸乙酯研究，发表在《柳叶刀》上。我的K 08导师加斯顿博士可以 GSNO气道检测在他的实验室，并有一个FDA监管核心和第11部分符合DCC的一部分， 他的计划项目补助金，可以协助IND和数据管理。UH临床研究 中心将提供FDA监管、研究人员和协调员核心支持本临床试验。我们 因此，具有用于测试吸入亚硝酸乙酯是否改善氧饱和指数的最佳情况， 患有呼吸衰竭的BPD婴儿。在这项原理证明研究结束时，我们希望能够 将这些发现应用于R 01或同等提案，将我的K 08发现转化为新的治疗方法 BPD战略。

Abstract/Summary: Bronchopulmonary dysplasia (BPD) is a chronic cardiopulmonary complication among survivors of preterm birth, with more than 10,000 new diagnoses in the US each year and healthcare costs estimated to exceed $2.5 billion. During my NHLBI K08, I have shown that pharmacologic inhibition or genetic deletion of the S- nitrosothiol catabolic enzyme, S-nitrosoglutathione reductase (GSNO reductase), prevents the development of all aspects of hyperoxic murine BPD including pulmonary vascular features. Moreover, increased airway GSNO reverses the BPD airway hyperreactivity and promotes bronchodilation in these mice. The GSNO- repleting agent, inhaled ethyl nitrite, has been used safely and successfully to treat pulmonary hypertension in mechanically ventilated human newborns. Here, I propose a pilot study using inhaled ethyl nitrite to treat hypoxic respiratory failure in human infants with BPD. Unlike inhaled nitric oxide (iNO), ethyl nitrite rapidly and robustly increases pulmonary GSNO levels in animal models, and should serve to reverse the bronchospasm and ventilation/perfusion mismatch that characterize BPD. I believe this preliminary study will be a particularly valuable clinical application of my K08 data, as other novel treatments for respiratory failure have not been developed for respiratory failure in BPD. As our primary clinical outcome variable, we will have power (>0.9) to detect a 41% (+ 27) improvement in pre/post oxygen saturation index with a 4 hour treatment of inhaled ethyl nitrite. We have a busy NICU at UH Rainbow Babies and Children's Hospital, with more than 25 infants/year with BPD that would be eligible for this two year pilot. We are also fortunate to have investigators on campus familiar with ethyl nitrite use in humans, Drs. James Reynolds and Jonathan Stamler. Of note, Dr. Stamler was the lead investigator in the initial neonatal ethyl nitrite study, published in The Lancet. My K08 mentor, Dr. Gaston, can perform the requisite GSNO airway assays in his laboratory, and has an FDA regulatory core and part 11-compliant DCC as part of his Program Project Grant that can assist with the IND and data management. The UH Clinical Research Center will provide FDA regulatory, research staffing, and coordinator cores to support this clinical trial. We therefore have an optimal situation for testing whether inhaled ethyl nitrite improves oxygen saturation index in infants with BPD who have respiratory failure. At the end of this proof of principle study, we hope to be able to apply these findings to an R01 or equivalent proposal to translate my K08 findings into a novel treatment strategy for BPD.