Pulmonary hypertension is a significant clinical problem in the neonate that is required to three structural abnormalities: maladaptation, maldevelopment, and pulmonary hypoplasia. They hypoplastic lung is characterized by decreases in vascular development that parallels those seen in the underdeveloped epithelium. While the advent of nitric oxide (NO) treatment has resulted in improved outcomes for patients with maladaptation and maldevelopment, patients with pulmonary hypoplasia are refractory to NO treatment and have the worst prognosis. Much effort has been expanded in elucidating the factors that regulate lung growth, but most of these studies have focused on the development of the lung epithelium and its production of pulmonary surfactant. A consistent observation has been that epithelial development is absolutely dependent on an interaction with pulmonary mesenchyme. In contrast, surprisingly little is known about the molecular regulation of the lung vasculature, especially during the earliest periods of development. The underlying hypothesis of this proposal is that the proliferation and differentiation of endothelial cells in the developing lung are dependent on an interaction with the epithelium. In this proposal they will first detail pulmonary vascular development in vivo. They will determine when vasculogenesis begins, and how it proceeds over the course of gestation; these results will be correlated with those obtained for human samples. Using several culture systems, they will then directly test their development, both in the early- and late-gestation lung, and determine how this process is affected by a number of hormone growth factors, and cytokines. Vascular endothelial growth factor (VEGF) is likely to play a role in normal vascular development in the lung. They will detail the temporal and spatial pattern of express of VEGF, and determine how this is regulated in vitro. They will then determine the importance of VEGF expression to normal vascular development. They will use molecular techniques to genetically manipulate an increase or decrease in VEGF expression, as well as compromise the ability of one VEGF receptor molecule to function. In the final portion of this project they will apply all of what they have learned to a rat model of congenital diaphragmatic hernia (CDH) that results in significant pulmonary hypoplasia. They will assess in this model whether the observed hypoplasia results from an inherent defect in the lung, or is necessarily secondary to CDH. These results will be correlated with observations will make in hypoplastic lung samples from human infants with CDH. At the completion of this project they expect to have substantially increased our knowledge of the molecular regulation of pulmonary vasculature development. This knowledge will undoubtedly prove useful in the prevention and treatment of diseases resulting from fetal lung immaturity and hypoplasia.
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