Elevated Vascular Endothelial Growth Factor is Correlated With Elevated Erythropoietin in Stable, Young Cystic Fibrosis Patients

The Division of Pulmonary Medicine, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614, USA.
Pediatric Pulmonology (Impact Factor: 2.3). 07/2011; 46(7):683-7. DOI: 10.1002/ppul.21428
Source: PubMed

ABSTRACT Angiogenesis is an important mechanism of airway remodeling in lung disease. We previously demonstrated that serum vascular endothelial growth factor (VEGF) is elevated in cystic fibrosis (CF) patients and declines with therapy for pulmonary exacerbation. We hypothesized that VEGF is elevated early in the course of CF and is associated with markers of tissue hypoxia. A prospective, single-visit evaluation of thirty stable infants and children with CF was performed. Serum was analyzed for VEGF and for other markers of tissue hypoxia (erythropoietin (EPO), insulin-like growth factor binding protein-1 (IGFBP-1)) and for inflammatory mediators (IL-1 beta, IL-6, IL-8, and tumor necrosis factor alpha (TNFα)) using Meso Scale multi-spot serum immunoassays. Measurements were correlated between assay groups; and with age in months and pulmonary function (FEV0.5 or FEV1). VEGF, EPO, TNFα and IL-8 were elevated compared to published normative values. VEGF levels were not significantly correlated with any inflammatory mediators. However, VEGF correlated with EPO (r=0.505; P<0.05). There was no correlation between lung function and markers of inflammation or tissue hypoxia. VEGF is elevated in young, stable infants and children suggesting angiogenesis as a contributing mechanism for early lung disease in CF. VEGF elevation does not show significant correlation with inflammatory mediators known to be increased in CF, but is significantly correlated with EPO levels. We propose that VEGF elevation and angiogenesis contribute to early lung disease and may result from a direct tissue hypoxia pathway in CF.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The chronic infection and inflammation of cystic fibrosis (CF) lung disease causes a progressive decline of lung function resulting in daily symptoms such as cough and sputum production. There are intermittent episodes of acute worsening of symptoms, more commonly referred to as pulmonary exacerbations. Despite this being a common event, there is still no standardized definition of an exacerbation. A recent set of guidelines from the CF Foundation Pulmonary Therapies Committee on the treatment of exacerbations noted the paucity of data supporting commonly used therapies. This review describes our current understanding of pulmonary exacerbations and the therapies used to treat them. The treatment of an exacerbation is intended to resolve the worsened symptoms and to restore the lung function that is commonly lost in the acute presentation. A most striking finding is the observation that for many patients there is no restoration of lung function, suggesting we either need better therapies to prevent exacerbations or better treatment of exacerbations. We have established recommendations on specific treatment of a pulmonary exacerbation and have outlined the areas where we need better information on appropriate therapies. Once we have a standardized definition of an exacerbation, we can proceed with clinical trials of therapies specific for its treatment.
    Current opinion in pulmonary medicine 08/2011; 17(6):442-7. DOI:10.1097/MCP.0b013e32834b8c04 · 2.96 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms of hypoxic injury to the developing human brain are poorly understood, despite being a major cause of chronic neurodevelopmental impairments. Recent work in the invertebrate Caenorhabditis elegans has shown that hypoxia causes discrete axon pathfinding errors in certain interneurons and motorneurons. However, it is unknown whether developmental hypoxia would have similar effects in a vertebrate nervous system. We have found that developmental hypoxic injury disrupts pathfinding of forebrain neurons in zebrafish (Danio rerio), leading to errors in which commissural axons fail to cross the midline. The pathfinding defects result from activation of the hypoxia-inducible transcription factor (hif1) pathway and are mimicked by chemical inducers of the hif1 pathway or by expression of constitutively active hif1α. Further, we found that blocking transcriptional activation by hif1α helped prevent the guidance defects. We identified ephrinB2a as a target of hif1 pathway activation, showed that knock-down of ephrinB2a rescued the guidance errors, and showed that the receptor ephA4a is expressed in a pattern complementary to the misrouting axons. By targeting a constitutively active form of ephrinB2a to specific neurons, we found that ephrinB2a mediates the pathfinding errors via a reverse-signaling mechanism. Finally, magnesium sulfate, used to improve neurodevelopmental outcomes in preterm births, protects against pathfinding errors by preventing upregulation of ephrinB2a. These results demonstrate that evolutionarily conserved genetic pathways regulate connectivity changes in the CNS in response to hypoxia, and they support a potential neuroprotective role for magnesium.
    PLoS Genetics 04/2012; 8(4):e1002638. DOI:10.1371/journal.pgen.1002638 · 8.17 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Peribronchial angiogenesis may occur in cystic fibrosis (CF) and vascular angiogenic growth factor (VEGF)-A regulates angiogenesis in airways.Peribronchial vascularity and VEGF-A expression were examined using immunocytochemistry and morphometric analysis in lung sections obtained in 10 CF patients at transplantation vs. 10 Control non-smokers, and in two strains of Cftr-deficient mice vs. wildtype littermates. Airway epithelial NCI-H292 cells and primary cultures of non-CF human airway epithelial cells (HAEC) were treated with CFTR inhibitors (CFTR-inh(172) or PPQ-102) or transfected with a CFTR siRNA with or without a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Concentrations of VEGF-A and phosphorylated EGFR were measured by ELISA.Peribronchial vascularity was increased in CF patients, but not in Cftr-deficient mice. VEGF-A immunostaining was localized to airway epithelium and was increased in CF patients and in Cftr-deficient mice. In cultured airway epithelial cells, treatment with CFTR-inhibitors or transfection with CFTR siRNA induced a two-fold increase in VEGF-A production. CFTR inhibitors triggered epidermal growth factor receptor (EGFR) phosphorylation that was required for VEGF-A synthesis.CF airways at transplantation showed increased peribronchial vascularity and epithelial VEGF-A expression. CFTR dysfunction triggered epithelial synthesis of VEGF-A, which may contribute to vascular remodeling.
    European Respiratory Journal 03/2013; 42(6). DOI:10.1183/09031936.00164212 · 7.13 Impact Factor
Show more