Recombinant human VEGF treatment enhances alveolarization after hyperoxic lung injury in neonatal rats

Abstract

-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...

Neonatal Hyperoxia Causes Pulmonary Vascular Disease and Shortens Life Span in Aging Mice

“…9 -11 Blocking VEGF signaling disrupts postnatal alveolar development, [12][13][14] and VEGF gene therapy can partially protect the developing rat lung against hyperoxia. 15,16 Besides VEGF, the number of circulating endothelial cell precursors found in blood and lung is reduced in neonatal mice exposed to hyperoxia 17 and, when restored, can attenuate murine models of BPD. 18,19 Collectively, a large body of data suggests that alveolar simplification and pulmonary hypertension seen in infants dying with BPD may be caused by oxidative stress disrupting microvascular development.…”

Neonatal Hyperoxia Enhances the Inflammatory Response in Adult Mice Infected with Influenza A Virus

“…Intriguingly, some of these changes are permanent, as normal lung structure and function are not restored when newborn animals are returned to room air (9)(10)(11). Hyperactive airways with increased thickness of the underlying smooth muscle have also been reported in 21-day-old rats exposed to and recovered from greater than 95% oxygen (12,13).…”

Pulmonary Epithelial Neuropilin-1 Deletion Enhances Development of Cigarette Smoke–induced Emphysema

“…Nrp1 may modulate the balance between VEGF and Sema3 signaling to alter cell proliferation and death in nonepithelial cell types (17,26). Both Nrp1 ligands, VEGF, and Sema3A, have independently been shown to contribute to alveolar septation (24,(27)(28)(29)(30) and vascular patterning (23,27,31), and human (32,33), animal (34)(35)(36)(37), and in vitro (38) studies support a possible role for VEGF in protection from acute lung injury and preservation of alveolar cell survival (39). Of note, it was shown that expression of Nrp1 protein was reduced in the lungs from smokers with spirometric evidence of COPD compared with smokers who had normal lung function and nonsmoking control subjects (40).…”