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.
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.
