-VEGF signaling inhibition decreases alveolar and vessel growth in the developing lung, suggesting that impaired VEGF signaling may contribute to decreased lung growth in bronchopulmonary dysplasia (BPD). Whether VEGF treatment improves lung structure in experimental models of BPD is unknown. The objective was to determine whether VEGF treatment enhances alveolarization in infant rats after hyperoxia. Two-day-old Sprague-Dawley rats were placed into hyperoxia or room air (RA) for 12 days. At 14 days, rats received daily treatment with rhVEGF-165 or saline. On day 22, rats were killed. Tissue was collected. Morphometrics was assessed by radial alveolar counts (RAC), mean linear intercepts (MLI), and skeletonization. Compared with RA controls, hyperoxia decreased RAC (6.1 Ϯ 0.4 vs. 11.3 Ϯ 0.4, P Ͻ 0.0001), increased MLI (59.2 Ϯ 1.8 vs. 44.0 Ϯ 0.8, P Ͻ 0.0001), decreased nodal point density (447 Ϯ 14 vs. 503 Ϯ 12, P Ͻ 0.0004), and decreased vessel density (11.7 Ϯ 0.3 vs. 18.9 Ϯ 0.3, P Ͻ 0.001), which persisted despite RA recovery. Compared with hyperoxic controls, rhVEGF treatment after hyperoxia increased RAC (11.8 Ϯ 0.5, P Ͻ 0.0001), decreased MLI (42.2 Ϯ 1.2, P Ͻ 0.0001), increased nodal point density (502 Ϯ 7, P Ͻ 0.0005), and increased vessel density (23.2 Ϯ 0.4, P Ͻ 0.001). Exposure of neonatal rats to hyperoxia impairs alveolarization and vessel density, which persists despite RA recovery. rhVEGF treatment during recovery enhanced vessel growth and alveolarization. We speculate that lung structure abnormalities after hyperoxia may be partly due to impaired VEGF signaling. bronchopulmonary dysplasia; lung development; vascular endothelial growth factor; angiogenesis BRONCHOPULMONARY DYSPLASIA (BPD) is the chronic lung disease of infancy that follows ventilator and oxygen therapy for respiratory distress syndrome after premature birth (37). Although the mechanisms that cause BPD are not completely understood, surfactant deficiency, ventilator-induced lung injury, oxygen toxicity, and inflammation are important pathogenic factors (21). Traditionally, BPD has been characterized by severe chronic lung injury with striking fibrosis and cellular proliferation. With advancements in perinatal care including exogenous surfactant administration, improved ventilator management, and antenatal steroids, the clinical course and lung histology of BPD have changed. Infants with BPD now have less severe acute respiratory disease, and at autopsy, lung histology is characterized by arrested lung development including alveolar simplification and dysmorphic vascular growth (1,18,21,37).Mechanisms that impair lung growth and cause persistent abnormalities in lung structure in premature infants with BPD remain poorly understood. Recently, experimental studies have shown that growth of the pulmonary circulation and alveolarization are closely coordinated, as demonstrated by findings that disruption of angiogenesis impairs lung structure (20). Treatment of neonatal rats with antiangiogenic agents, including fumagillin and thalidomide...

Platelet-derived growth factor (PDGF) is a potent smooth muscle cell mitogen that may contribute to smooth muscle hyperplasia during the development of chronic pulmonary hypertension (PH). We studied changes in PDGFalpha- and beta-receptor and ligand expression in lambs with chronic intrauterine PH induced by partial ligation of the ductus arteriosus (DA) at gestational age 124-128 days (term = 147 days). Western blot analysis performed on whole lung homogenates from PH animals after 8 days of DA ligation showed a twofold increase in PDGFalpha- and beta-receptor proteins compared with age-matched controls (P < 0.05). Lung PDGF-A and -B mRNA expression did not differ between PH and control animals. We treated PH animals with NX1975, an aptamer that selectively inhibits PDGF-B, by infusion into the left pulmonary artery for 7 days after DA ligation. NX1975 reduced the development of muscular thickening of small pulmonary arteries by 47% (P < 0.05) and right ventricular hypertrophy (RVH) by 66% (P < 0.02). Lung PDGFalpha- and beta-receptor expression is increased in perinatal PH, and NX1975 reduces the increase in wall thickness of small pulmonary arteries and RVH in this model. We speculate that PDGF signaling contributes to structural vascular remodeling in perinatal PH and that selective PDGF inhibition may provide a novel therapeutic strategy for the treatment of chronic PH.

Infants with severe bronchopulmonary dysplasia-associated pulmonary hypertension have increased morbidity and mortality through 1 year of corrected age. This highlights the need for improved diagnostic practices and prospective studies evaluating treatments for this high-risk population.

Tracheobronchomalacia is common in neonates with bronchopulmonary dysplasia who undergo bronchoscopy and is associated with longer and more complicated hospitalizations.