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 PAin 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 poorlyunderstood. It has long been assumed that the expanded population of cells in the thickened PA originatesvia proliferation of resident lung fibroblasts and smooth muscle cells (SMC), as well as via differentiation ofresident lung fibroblasts into myofibroblasts. However, new experimental evidence suggests a non-residentsource for tissue mesenchymal cells (fibroblasts, myofibroblasts, SMC). Among different types ofmesenchymal progenitors, a subpopulation of circulating leukocytes, termed fibrocytes, has been proposedas a major contributor to the structural tissue remodeling and fibrosis in healing wounds, bleomycin-inducedlung injury, and asthma. We have recently demonstrated the robust PA accumulation of fibrocytes in chronichypoxic neonatal pulmonary hypertension and showed that these circulating cells are crucial for thepulmonary vascular structural remodeling seen in that setting. Our preliminary data suggest that circulatingfibrocytes also contribute to the vascular remodeling observed in neonatal rats and mice exposed tohyperoxia (animal models of BPD). Preliminary data support a role for oxidant imbalances and endothelin inthe recruitment of fibrocytes to the lung. We therefore propose to test the overall hypothesis that, in thesetting of hyperoxia-induced lung injury, circulating fibrocytes are recruited to the lung where they act asprogenitors of mesenchymal cells, and contribute significantly to pulmonary vascular remodeling andpulmonary hypertension, and that EC-SOD and ET-1 play critical roles in this process. We will determine themechanisms involved in the recruitment of fibrocytes to the lung and lung vasculature and their contributionto remodeling using both pharmacologic strategies and genetic models to manipulate expression ofmolecules potentially involved in fibrocyte recruitment and differentiation. These experiments will result in abetter understanding of vascular changes in BPD and, ultimately in the development of selective therapeuticstrategies to decrease the recruitment of circulating mesenchymal progenitors to the hyperoxic lung in human infants with BPD.
Showing the most recent 10 out of 92 publications
