Novel Means to Establish Free Radical Balance in the Neonatal Premature Lung

描述（由申请方提供）：呼吸窘迫综合征（RDS）是早产儿的一种危及生命的疾病，其中肺在发育上对子宫外功能没有准备，并迅速发展为水肿、依从性差、肺动脉高压（PAH）和气体交换受损。目前的护理标准仅限于低容量机械通气和外源性气管内给予表面活性剂。尽管有最佳的医疗管理，50%的体重< 1 kg的极低出生体重儿在出生后28天仍需要补充氧气。该基准符合支气管肺发育不良（BPD）的诊断，BPD是一种肺泡发育不良、间质纤维化和慢性肺功能不全的疾病。这些患者中有相当一部分将长期需要补充O2，达到严重的呼吸障碍程度，对生活质量产生深远影响，并需要因肺炎和细支气管炎而频繁和终身住院。我们目前对RDS和BPD的理解与肺实质内过量O2-和一氧化氮（NO）缺乏所产生的损伤机制一致。这些自由基种类的失衡对肺泡形成、肺血管重塑、间质炎症、气体交换和肺力学具有多重影响。为了解决这一未满足的需求，我们正在开发R-100，这是一种化学稳定的氧化还原剂，由释放NO的有机硝酸盐和吡咯烷氮氧化物的共价键形成，该吡咯烷氮氧化物用作O2-歧化酶（SOD）模拟物，过氧化氢酶模拟物和过氧亚硝酸盐（ONOO-）分解催化剂。氮氧化物催化部分用作抗氧化剂贮库，在其羟胺和自由基形式之间循环。氮氧自由基通过两种不同的催化途径催化O2-歧化反应，包括还原和氧化反应机制：1）R-100容易被质子化的O2-氧化，即？OOH，以产生氧代铵阳离子（II），这反过来又氧化另一个O2-分子O2。2)或者，R-100可以在催化过程中与O2-反应，该催化过程的特征在于氮氧自由基和羟胺（III）的稳态分布以及O2和H2 O2的连续形成。如此产生的H2 O2然后通过氮氧化物的过氧化氢酶活性转化为H2O。结合起来，这些功能允许R-100去除有毒的活性氧物质并提供NO，而不会产生ONOO-的混淆效应。R-100对正常血压对照大鼠的全身血压没有影响，对野百合碱诱导的大鼠PAH也没有影响，但在3种不同的PAH绵羊模型中作为选择性肺血管扩张剂有效。在慢性大鼠野百合碱模型中，R-100延迟治疗可几乎完全阻止和逆转肺纤维化和肺泡炎症的进展，并阻断血管肥大和减弱PAH。具体目标：建立R-100减轻博莱霉素诱导的新生大鼠BPD模型肺血管和肺泡结构变化的实验研究。R-100给药3周，该模型系统的特征为进行性肺纤维化、PAH和肺泡发育不良。证明R-100增加肺泡密度并减少肺纤维化、肺小动脉平滑肌肥大和右心室质量将证明在早产羔羊中进行确证性研究是合理的。 公共卫生相关性：早产通常与急性呼吸道疾病相关，该急性呼吸道疾病可能转化为长期的致残性肺损伤，称为支气管肺发育不良（“BPD”）。目前还没有特定的现有疗法可以可靠地阻止BPD的发展。我们正在开发一种针对这种疾病基本机制的新药，并将在临床相关的早产儿肺病动物模型中测试这种药物。

DESCRIPTION (provided by applicant): Respiratory Distress Syndrome (RDS) is a life-threatening condition of the premature infant, wherein the lung is developmentally unprepared for ex utero function and rapidly develops edema, poor compliance, pulmonary arterial hypertension (PAH), and impaired gas exchange. Current standard of care is limited to low volume mechanical ventilation and the exogenous endotracheal administration of surfactant. In spite of optimal medical management, 50% of very low birthweight infants, weighing < 1 kg, will continue to require supplemental oxygen at 28 days of life. This benchmark qualifies for a diagnosis of bronchopulmonary dysplasia (BPD), a disease of hypoalveolarization, interstitial fibrosis, and chronic pulmonary insufficiency. A significant minority of these patients will develop a prolonged requirement for supplemental O2, to the extent of a crippling respiratory impairment with profound effects on quality of life and necessitating frequent and lifelong hospitalizations for pneumonia and bronchiolitis. Our current understanding of RDS and BPD is consistent with a mechanism of injury produced by an excess of O2- and a deficiency of nitric oxide (NO) within the lung parenchyma. The imbalance of these free radical species has multiple effects on alveolarization, pulmonary vascular remodeling, interstitial inflammation, gas exchange, and pulmonary mechanics. To address this unmet need, we are developing R-100, a chemically stable redox agent formed from the covalent linkage of an organic nitrate that releases NO, and a pyrrolidine nitroxide that acts as an O2- dismutase (SOD) mimetic, a catalase mimic, and a peroxynitrite (ONOO-) decomposition catalyst. The nitroxide catalytic moiety serves as an anti-oxidant depot, cycling between its hydroxylamine and free radical form. Nitroxides catalyze O2- dismutation through 2 different catalytic pathways including reductive and oxidative reaction mechanisms: 1) R-100 is readily oxidized by protonated O2-, i.e. ?OOH, to yield oxoammonium cation (II), which in turn oxidizes another O2- to molecular O2. 2) Alternatively, R-100 may react with O2- in a catalytic process characterized by a steady state distribution of nitroxide and hydroxylamine (III) and a continuous formation of O2 and H2O2. The H2O2 so produced is then converted to H2O by the catalase activity of the nitroxide. In combination, these functionalities allow R-100 to remove toxic reactive oxygen species and deliver NO without the confounding effect of producing ONOO-. R-100 has no effect on systemic blood pressure in normotensive control rats nor in monocrotaline-induced PAH in rats, but is effective as a selective pulmonary vasodilator in 3 distinct ovine models of PAH. In a chronic rat monocrotaline model, delayed therapy with R-100 provided near complete arrest and reversal of the progression in pulmonary fibrosis and alveolar inflammation, and blocked vascular hypertrophy and attenuated PAH. Specific Aim: Establish that R-100 attenuates changes of pulmonary vascular and alveolar structure in a model of BPD induced by bleomycin treatment of neonatal rats. R-100 will be administered for 3 weeks, a period characterized in this model system by progressive lung fibrosis, PAH, and hypoalveolarization. Demonstration that R-100 increases alveolar density and reduces pulmonary fibrosis, pulmonary arteriolar smooth muscle hypertrophy, and right ventricular mass will justify progression to a confirmatory study in premature lambs. PUBLIC HEALTH RELEVANCE: Premature birth is frequently associated with an acute respiratory disease that may convert to a long term crippling lung impairment, known as bronchopulmonary dysplasia ("BPD"). There are no specific existing therapies that can reliably block the development of BPD. We are developing a novel drug that targets the basic mechanisms of this condition and will test this agent in a clinically-relevant animal model of premature lung disease.