In many infants with BPD abnormal pulmonary microvascular development and pulmonary artery (PA) structural remodeling are observed. The latter process includes abnormal muscularization of resistance PA in the lung periphery, as well as medial hypertrophy, adventitial thickening and fibrosis in more proximal PA. The causes of abnormal pulmonary vascular development and structural remodeling in BPD are poorly understood. It has long been assumed that the expanded population of cells in the thickened PA originates via proliferation of resident lung fibroblasts and smooth muscle cells (SMC), as well as via differentiation of resident lung fibroblasts into myofibroblasts. However, new experimental evidence suggests a non-resident source for tissue mesenchymal cells (fibroblasts, myofibroblasts, SMC). Among different types of mesenchymal progenitors, a subpopulation of circulating leukocytes, termed fibrocytes, has been proposed as a major contributor to the structural tissue remodeling and fibrosis in healing wounds, bleomycin-induced lung injury, and asthma. We have recently demonstrated the robust PA accumulation of fibrocytes in chronic hypoxic neonatal pulmonary hypertension and showed that these circulating cells are crucial for the pulmonary vascular structural remodeling seen in that setting. Our preliminary data suggest that circulating fibrocytes also contribute to the vascular remodeling observed in neonatal rats and mice exposed to hyperoxia (animal models of BPD). Preliminary data support a role for oxidant imbalances and endothelin in the recruitment of fibrocytes to the lung. We therefore propose to test the overall hypothesis that, in the setting of hyperoxia-induced lung injury, circulating fibrocytes are recruited to the lung where they act as progenitors of mesenchymal cells, and contribute significantly to pulmonary vascular remodeling and pulmonary hypertension, and that EC-SOD and ET-1 play critical roles in this process. We will determine the mechanisms involved in the recruitment of fibrocytes to the lung and lung vasculature and their contribution to remodeling using both pharmacologic strategies and genetic models to manipulate expression of molecules potentially involved in fibrocyte recruitment and differentiation. These experiments will result in a better understanding of vascular changes in BPD and, ultimately in the development of selective therapeutic strategies to decrease the recruitment of circulating mesenchymal progenitors to the hyperoxic lung in human infants with BPD.
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