Bronchopulmonary Dysplasia (BPD) is a chronic lung disease of premature infants that results from oxygen and ventilator therapy. In BPD, the lung is chronically injured and healing is often incomplete. Because BPD patients are premature, the injury-repair cycle can impair normal lung development. The distal lung capillaries, which are essential for gas exchange, are not fully developed at birth in premature infants who are at risk for BPD. Poor development of the distal lung capillaries is characteristic of this disease. Capillary development is under the tight control of several families of angiogenic factors, including Vascular Endothelial Growth Factor (VEGF) and the Angiopoietins. These factors interact and their correct temporal and spatial expression pattern is essential for normal capillary development. Uncoordinated expression of these factors can impede capillary formation and result in capillary regression. VEGF in the distal lung epithelium is decreased in human and baboon BPD, but the mechanisms are not known. The role of Angiopoietins in lung development and BPD are also not known, but injury-related expression of specific Angiopoietins can result in capillary regression, particularly when VEGF is low. Our overall hypothesis is that BPD is associated with disruption of the normal program of angiogenic factor expression, resulting in poor capillary development. The first Specific Aim investigates aberrant expression of several regulators of VEGF that may be altered in BPD, including p53, and Hypoxia-Inducible-Factors (HIFs). Cell-specific co-localization of these factors with VEGF is investigated with dual fluorescent immunohistochemistry in the second Specific Aim. The third Specific Aim examines cell-specific expression of Angiopoietins and phorphorylation of their receptor TIE-2 which are required for normal capillary formation. Potential therapies for BPD must ameliorate disrupted capillary development. The fourth Specific Aim presents a plan for evaluating distal capillary development and angiogenic factor expression in collaboration with other investigators in the Collaborative Program in BPD. New data from this proposal will be essential for developing novel therapies for BPD.
| Pierce, Richard A; Joyce, Belinda; Officer, Susan et al. (2007) Retinoids increase lung elastin expression but fail to alter morphology or angiogenesis genes in premature ventilated baboons. Pediatr Res 61:703-9 |
| D'Angio, Carl T; Maniscalco, William M (2004) Bronchopulmonary dysplasia in preterm infants: pathophysiology and management strategies. Paediatr Drugs 6:303-30 |
