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，其肺部发育不足以适应体外功能，并迅速发展为水肿、顺应性差、肺动脉高压(PAH)和气体交换障碍。目前的护理标准仅限于低容量机械通气和外源性表面活性物质的气管内给药。尽管有最佳的医疗管理，50%的极低出生体重儿，体重1公斤，在出生28天时仍需要补充氧气。这一基准符合诊断支气管肺发育不良(BPD)的条件，BPD是一种肺泡减少、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人将长期需要补充氧气，以至于严重的呼吸损伤，严重影响生活质量，并需要因肺炎和毛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O2-过多和一氧化氮(NO)缺乏所致损伤的机制是一致的。这些自由基的失衡对肺泡化、肺血管重塑、间质炎症、气体交换和肺力学有多方面的影响。为了满足这一未得到满足的需求，我们正在开发R-100，这是一种化学上稳定的氧化还原剂，由释放NO的有机硝酸盐和吡咯烷氮氧化物共价连接而成，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。氮氧化物催化部分作为抗氧化剂储存库，在其羟胺和自由基之间循环。氮氧化物通过两种不同的催化途径催化O2-歧化，包括还原和氧化反应机制：1)R-100很容易被质子化的O2-氧化生成氧氨阳离子(II)，进而将另一个O2-氧化成分子O2。2)或者，R-100可能与O2-在催化过程中反应，其特征是氮氧化物和羟胺(III)的稳定分布以及O2和H2O2的连续生成。这样产生的过氧化氢然后通过氮氧化物的过氧化氢酶活性转化为水。这些功能结合在一起，使R-100能够去除有毒的活性氧物种并提供NO，而不会产生ONOO-的混杂影响。R-100对正常血压对照组大鼠的全身血压和野百合碱诱导的大鼠肺动脉高压均无影响，但对3种不同的绵羊PAH模型有选择性的肺血管扩张剂作用。在慢性大鼠野百合碱模型中，R-100的延迟治疗几乎完全阻止和逆转了肺纤维化和肺泡炎的进展，并阻止了血管肥大和减轻PAH。具体目的：建立博莱霉素致BPD新生大鼠肺血管和肺泡结构改变的模型，观察R-100对BPD的保护作用。R-100将用药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、PAH和肺泡减少。证明R-100增加肺泡密度和减少肺纤维化、肺小动脉平滑肌肥大和右室包块将证明在早产羔羊中进行验证性研究是合理的。 公共卫生相关性：早产经常与一种急性呼吸系统疾病有关，这种疾病可能会转变为长期的严重肺损伤，称为支气管肺发育不良(BPD)。目前还没有特定的治疗方法可以可靠地阻止BPD的发展。我们正在开发一种针对这种疾病的基本机制的新药，并将在临床相关的早产儿肺部疾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.