Ambient oxygen concentration and vascular endothelial growth factor (VEGF)-A are vital in lung development. Since hypoxia stimulates VEGF-A production and hyperoxia reduces it, we hypothesized that VEGF-A down-regulation by exposure of airways to hyperoxia may result in abnormal lung development. An established model of in vitro rat lung development was used to examine the effects of hyperoxia on embryonic lung morphogenesis and VEGF-A expression. Under physiologic conditions, lung explant growth and branching is similar to that seen in vivo. However, in hyperoxia (50% O 2 ) the number of terminal buds and branch length was significantly reduced after 4 d of culture. This effect correlated with a significant increase in cellular apoptosis and decrease in proliferation compared with culture under physiologic conditions. mRNA for Vegf164 and Vegf188 was reduced during hyperoxia and addition of VEGF165, but not VEGF121, to explants grown in 50% O 2 resulted in partial reversal of the decrease in lung branching, correlating with a decrease in cell apoptosis. Thus, hyperoxia suppresses VEGF-A expression and inhibits airway growth and branching. The ability of exogenous VEGF165 to partially reverse apoptotic effects suggests this may be a potential approach for the prevention of hyperoxic injury. T he lung develops by outgrowth, elongation, and reiterated subdivision of the distal embryonic lung bud (1). Rodent embryonic lung explants appear to retain this stereotypic pattern of growth, thus allowing investigation of the pathways that can regulate lung development and how lung maturation may be disrupted under conditions of cellular stress.In the mouse, lung branching morphogenesis begins at embryonic day 9.5 (E9.5) (2) and is regulated by growth factors, cytokines, and the ambient oxygen concentration (3). Low oxygen tensions are a persistent feature of embryonic life (4) and experiments in explanted lungs reveal that oxygen concentrations between 3% and 5% stimulate the process of bud branching and cell proliferation compared with ambient oxygen tension (5). Under similar conditions, cultured developing kidneys exhibit enhanced growth and greater numbers of tubules and blood vessels (6).The ability of hypoxia to stimulate organ development has been attributed to the transcriptional up-regulation of hypoxiainducible factor (HIF)-dependent pathways such as Vegf-A (7) and its receptors 1 (Vegf-r1 or Flt-1) and 2 (Vegf-r2 or Flk-1) (8). VEGF-A is secreted by multiple cell types, including the airway epithelium, and activates VEGF receptors on nearby endothelial cells, stimulating vascular growth. Both Vegf-r1 and Vegf-r2 have been localized to endothelial cells and are expressed throughout development. Recent studies have shown that Vegf-A can also play a role in epithelial cell morphogenesis in both the lung and the kidney (9,10). This may be due to an indirect effect of VEGF-stimulated vascular development on adjacent epithelial structures, or a direct effect of VEGF-A on the epithelial cells themselves.Alte...

We report undescribed pulmonary findings in a child with mucolipidosis II (ML-II). Children with ML-II bear significant pulmonary morbidity that may include extensive pulmonary fibrosis, persistent hemosiderosis as well as pulmonary airway excrescences as they reach preschool age.

We report a 19-year-old man with pulmonary squamous cell carcinoma (SCC) who had a history of vertebral, anal, cardiac, tracheal, esophageal, renal, and radial limb defects (VACTERL) association and tracheoesophageal fistula (TEF) + esophageal atresia (EA) repair as an infant. Children that undergo TEF + EA repair may have an increased risk for developing cancer as they reach adulthood.

BackgroundPrevious work in our laboratory demonstrated that hyperoxia suppressed the expression of vascular endothelial growth factor (VEGF) by the embryonic lung, leading to increased epithelial cell apoptosis and failure of explant airway growth and branching that was rescued by the addition of Vegf165. The aims of this study were to determine protective pathways by which VEGF isoforms attenuate hyperoxic lung growth retardation and to identify the target cell for VEGF action.MethodsTimed pregnant CD-1 or fetal liver kinase (FLK1)-eGFP lung explants cultured in 3% or 50% oxygen were treated ± Vegf121, VEGF164/Vegf165 or VEGF188 in the presence or absence of anti-rat neuropilin-1 (NRP1) antibody or GO6983 (protein kinase C (PKC) pan-inhibitor) and lung growth and branching quantified. Immunofluorescence studies were performed to determine apoptosis index and location of FLK1 phosphorylation and western blot studies of lung explants were performed to define the signaling pathways that mediate the protective effects of VEGF.ResultsHeparin-binding VEGF isoforms (VEGF164/Vegf165 and VEGF188) but not Vegf121 selectively reduced epithelial apoptosis and partially rescued lung bud branching and growth. These protective effects required NRP1-dependent FLK1 activation in endothelial cells. Analysis of downstream signaling pathways demonstrated that the VEGF-mediated anti-apoptotic effects were dependent on PKC activation.ConclusionsVegf165 activates FLK1-NRP1 signaling in endothelial cells, leading to a PKC-dependent paracrine signal that in turn inhibits epithelial cell apoptosis.

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