In our population of VLBW infants, sepsis is frequently associated with thrombocytopenia and an elevation in MPV. However, fungal and Gram-negative pathogens are associated with a lower platelet count and more prolonged thrombocytopenia compared with Gram-positive pathogens. We conclude that common pathogens causing sepsis have different effects on platelet kinetics.

-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...

human VEGF treatment transiently increases lung edema but enhances lung structure after neonatal hyperoxia. Am J Physiol Lung Cell Mol Physiol 291: L1068 -L1078, 2006. First published July 7, 2006 doi:10.1152/ajplung.00093.2006.-Recent studies suggest that VEGF may worsen pulmonary edema during acute lung injury (ALI), but, paradoxically, impaired VEGF signaling contributes to decreased lung growth during recovery from ALI due to neonatal hyperoxia. To examine the diverse roles of VEGF in the pathogenesis of and recovery from hyperoxia-induced ALI, we hypothesized that exogenous recombinant human VEGF (rhVEGF) treatment during early neonatal hyperoxic lung injury may increase pulmonary edema but would improve late lung structure during recovery. Sprague-Dawley rat pups were placed in a hyperoxia chamber (inspired O2 fraction 0.9) for postnatal days 2-14. Pups were randomized to daily intramuscular injections of rhVEGF165 (20 g/kg) or saline (controls). On postnatal day 14, rats were placed in room air for a 7-day recovery period. At postnatal days 3, 14, and 21, rats were killed for studies, which included body weight and wet-to-dry lung weight ratio, morphometric analysis [including radial alveolar counts (RAC), mean linear intercepts (MLI), and vessel density], and lung endothelial NO synthase (eNOS) protein content by Western blot analysis. Compared with room air controls, hyperoxia increased pulmonary edema by histology and wet-to-dry lung weight ratios at postnatal day 3, which resolved by day 14. Although treatment with rhVEGF did not increase edema in control rats, rhVEGF increased wet-to-dry weight ratios in hyperoxia-exposed rats at postnatal days 3 and 14 (P Ͻ 0.01). Compared with room air controls, hyperoxia decreased RAC and increased MLI at postnatal days 14 and 21. Treatment with VEGF resulted in increased RAC by 181% and decreased MLI by 55% on postnatal day 14 in the hyperoxia group (P Ͻ 0.01). On postnatal day 21, RAC was increased by 176% and MLI was decreased by 58% in the hyperoxia group treated with VEGF. rhVEGF treatment during hyperoxia increased eNOS protein on postnatal day 3 by threefold (P Ͻ 0.05). We conclude that rhVEGF treatment during hyperoxia-induced ALI transiently increases pulmonary edema but improves lung structure during late recovery. We speculate that VEGF has diverse roles in hyperoxiainduced neonatal lung injury, contributing to lung edema during the acute stage of ALI but promoting repair of the lung during recovery. bronchopulmonary dysplasia; lung development; vascular endothelial growth factor; alveolarization; angiogenesis BRONCHOPULMONARY DYSPLASIA (BPD) is the chronic lung disease of infancy that follows ventilator and oxygen therapy for respiratory distress syndrome after premature birth (34). Although the mechanisms underlying BPD are not completely understood, surfactant deficiency, ventilator-induced lung injury, oxygen toxicity, infection, and inflammation are important pathogenic factors (19). Despite improvements in perinatal care over the past decade, the...

Exposure to hypoxia during the first weeks of life in newborn rats decreases vascular growth and alveolarization and causes pulmonary hypertension (PH). BAY 41-2272 is a novel direct activator of soluble guanylate cyclase independent of nitric oxide, effective as an acute pulmonary vasodilator in an animal model of persistent pulmonary hypertension of the newborn, but whether prolonged BAY 41-2272 therapy is effective in the setting of chronic PH is unknown. We hypothesize that BAY 41-2272 would prevent PH induced by chronic exposure to neonatal hypoxia. At 2 days of age, newborn rats were randomly exposed to hypoxia (FiO₂, 0.12) or room air, and received daily intramuscular treatment with BAY 41-2272 (1 mg/kg) or saline. After 2 weeks, rats were killed for assessment of right ventricular hypertrophy (RVH), wall thickness of small pulmonary arteries, vessels density, radial alveolar counts and mean linear intercepts. In comparison with control, hypoxia increased RVH and artery wall thickness, reduced vessels density, decreased radial alveolar counts and increased mean linear intercepts. In comparison with hypoxic controls, prolonged BAY 41-2272 treatment during chronic hypoxia reduced RVH (0.67 ± 0.03 vs. 0.52 ± 0.05; p < 0.05), and attenuated artery wall thickness (48.2 ± 2.8% vs. 35.7 ± 4.1 µm; p < 0.01). However, BAY 41-2272 did not change vessels density, radial alveolar counts or mean linear intercepts. We conclude that BAY 41-2272 prevents the vascular structural effects of PH and reduces RVH but does not protect from hypoxia-induced inhibition of alveolarization and vessel growth. We speculate that BAY 41-2272 may provide a new therapy for chronic PH.