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.
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