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

描述（由申请人提供）：呼吸窘迫综合征（RDS）是早产儿的一种危及生命的疾病，其中肺发育未准备好体外功能，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小容量机械通气和外源性气管内表面活性剂的管理。尽管有最佳的医疗管理，50%的极低出生体重婴儿（体重< 1公斤）在28天的生命中仍需要补充氧气。该指标可用于支气管肺发育不良（BPD）的诊断，BPD是一种低肺泡化、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发展为长期补充氧气的需要，达到严重的呼吸障碍的程度，对生活质量产生深远的影响，并需要经常和终身住院治疗肺炎和细支气管炎。我们目前对RDS和BPD的理解与肺实质内O2-过量和一氧化氮（NO）缺乏造成的损伤机制一致。这些自由基的失衡对肺泡化、肺血管重构、间质炎症、气体交换和肺力学有多重影响。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的有机硝酸盐的共价键和作为O2-歧化酶（SOD）模拟物、过氧化氢酶模拟物和过氧亚硝酸盐（ONOO-）分解催化剂的吡咯烷类氮氧化物形成。氮氧化物催化部分充当抗氧化剂仓库，在其羟胺和自由基形式之间循环。氮氧化物通过两种不同的催化途径催化O2-裂解，包括还原和氧化反应机制：1)R-100很容易被质子化的O2-氧化，即？OOH，生成氧铵阳离子（II），它又将另一个O2-氧化为O2分子。2) R-100也可能与O2-发生反应，其催化过程以氮氧化物和羟胺（III）的稳态分布和O2和H2O2的连续生成为特征。由此产生的H2O2通过过氧化氢酶的活性转化为H2O。结合起来，这些功能使R-100能够去除有毒的活性氧并提供NO，而不会产生ONOO-的混淆效应。R-100对正常对照大鼠的全身血压没有影响，对单罗塔林诱导的多环芳烃大鼠也没有影响，但在3种不同的多环芳烃羊模型中，R-100作为选择性肺血管扩张剂是有效的。在慢性大鼠单罗塔林模型中，R-100延迟治疗几乎完全阻止和逆转了肺纤维化和肺泡炎症的进展，阻断了血管肥大和减轻了PAH。具体目的：研究R-100对新生大鼠博来霉素致BPD模型肺血管和肺泡结构的影响。R-100将给药3周，在这个模型系统中，这段时间的特征是进行性肺纤维化、多环芳烃和低肺泡化。R-100增加肺泡密度，减少肺纤维化、肺小动脉平滑肌肥厚和右心室质量的证明，将证明在早产羔羊中进行确证性研究是合理的。

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.