In contrast to lung branching morphogenesis, studies of the mechanisms that regulate lung vascular development and that link capillary growth with alveolarization are relatively recent and limited in scope. Lack of information regarding lung vascular growth and its connection with alveolar growth is unfortunate, because developmental abnormalities of the pulmonary circulation contribute to the pathogenesis of several important neonatal cardiopulmonary disorders including pulmonary hypertension in the newborn. Further, there is growing recognition that the importance of understanding basic mechanisms of lung vascular growth in the context of human disease may be best highlighted in the setting of bronchopulmonary dysplasia (BPD). BPD is a significant health care problem associated with acute and long-term pulmonary consequences. Recent data from animal and clinical studies suggest that impaired vascular growth may contribute to abnormalities of lung architecture, especially decreased alveolarization, and thus play a critical role in the pathogenesis of BPD. However, little is known about the mechanisms of pulmonary vascular injury in the immature lung, the impact of this injury on growth and development of the lung, or its contribution to the pathogenesis of BPD and pulmonary hypertension. The overall goal of this proposal is to generate clinical and basic information that will provide insight into the mechanisms contributing to the pulmonary vascular abnormalities that characterize BPD, to evaluate currently available therapies aimed at reducing lung injury and restoring vascular and lung growth and to examine in animal models new approaches aimed at ameliorating perinatal lung injury and restoring vascular and lung growth. Three clinical and two basic projects are proposed. The clinical projects will evaluate the impact of inhaled nitric oxide (iNO) on BPD, the role of specific genetic factors in predisposing infants to BPD, and the development of improved techniques to assess the presence of pulmonary hypertension and the responses to therapy in infants with pulmonary hypertension. Two basic projects will dissect the mechanisms contributing to lung vascular remodeling in murine, rodent, and ovine models and evaluate the effects of novel pharmacologic agents on lung vascular disease in these models. The long-term goal is to utilize information derived from these models to develop new and improved therapies for the infant with BPD. (End of Abstract) INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1: Non-Invasive Inhaled NO In Premature Newborns (Kinsella, John) DESCRIPTION (provided by applicant): Inhaled nitric oxide (iNO) therapy has proven to be a safe and effective treatment for term newborns with PPHN and hypoxemic respiratory failure. Recent studies have focused on the potential role of iNO in the prevention of bronchopulmonary dysplasia (BPD), however, its effect on the pulmonary circulation in premature newborns has received less attention. Premature infants are particularly susceptible to the adverse effects of oxygen toxicity and lung inflammation which cause pulmonary parenchymal, airway, and pulmonary vascular injury, all of which contribute to the development of BPD and pulmonary hypertension. BPD remains a major cause of morbidity and mortality in premature newborns, and is characterized by chronic structural and functional pulmonary vascular abnormalities. Clinical trials of iNO in intubated premature newborns with hypoxemic respiratory failure have yielded conflicting results to date. Our multicenter trial of iNO in premature newborns (N=793) is near completion and will help clarify the role of iNO in this population of infants who require mechanical ventilation for hypoxemic respiratory failure, however, neonatologists are increasingly avoiding routine intubation and mechanical ventilation for even the most premature infants, opting instead to employ early, non-invasive continuous positive airway pressure (early CPAP, eCPAP) with the expectation that this mode of respiratory support will reduce acute lung injury and BPD. Unfortunately, preliminary observations have not demonstrated that this approach markedly reduces the development of BPD. Although eCPAP reduces the risk from VILI, it may not modify the injury caused by oxygen toxicity and lung inflammation in the immature lung. We hypothesize that low-dose iNO delivered non-invasively during eCPAP will reduce the incidence of BPD in premature newborns who do not require mechanical ventilation in the first 24 hours of life, and will reduce the early and late findings of pulmonary hypertension that characterize BPD. To test this hypothesis, we have designed a single-center randomized, controlled, masked pilot trial of non-invasive iNO treatment.
Specific aims of this study are: 1) to determine if iNO reduces the combined endpoint of BPD/mortality in premature newborns (500-1250 grams birth weight) who do not require intubation in the first 24 hours of life;and 2) to determine if non-invasive iNO treatment decreases early and late pulmonary vascular abnormalities in this population.
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