Sputum Vascular Endothelial Growth Factor Research Articles

Effects of high altitude and cold air exposure on airway inflammation in patients with asthma

AimsEighteen patients with asthma were evaluated during preparation to climb to extreme altitude in order to study the effects of low fractional inspired oxygen (FiO2), prolonged exposure to cold air...

Sputum VEGF level increases with treatment of COPD acute exacerbation

Introduction: The role of vascular endothelial growth factor (VEGF) in COPD pathogenesis has been studied widely; however the change in blood and airway VEGF levels during the treatment of an acute exacerbation has not been investigated. In this study we aimed to evaluate the changes in plasma and sputum VEGF levels during COPD exacerbation. Methods: 14 subjects (64±10 years) with established COPD participated in the study. Spontaneous sputa and EDTA-plasma samples were collected for VEGF measurement at admission to hospital due to an acute exacerbation of COPD (Anthonisen type I-II) and also at discharge from hospital. During hospitalization (8±1 days) patients were treated with systemic corticosteroids (n=12) and/or with antibiotics (n=7). VEGF concentration was measured by ELISA. Data are shown as mean±SD and analyzed with parametric tests. Results: Sputum VEGF levels positively correlated with FEV1 percent predicted (r=0.61, p=0.02) and FEV1/FVC (r=0.55, p=0.04) at baseline, while no relationship was observed between plasma VEGF level and clinical parameters. There was no correlation between sputum and plasma VEGF concentrations (p=0.65). Sputum level of VEGF increased significantly (6670±6252 pg/ml vs. 9735±6909 pg/ml, before vs. after treatment, p=0.04) following treatment, while there was no change in plasma VEGF levels (179±98 pg/ml vs. 173±93 pg/ml, before vs. after treatment p=0.73). Conclusion: Recovery from COPD exacerbation might be associated with increased airway VEGF level. Analysis of sputum but not plasma may reflect the changes in VEGF levels in COPD patients during exacerbation. The study was supported by National Scientific Research Fund (OTKA 68808) and Hungarian Respiratory Society grants.

Defect of Adaptation to Hypoxia in Patients With COPD Due to Reduction of Histone Deacetylase 7

Background:Hypoxia inducible factor (HIF)-1 plays an important role in cellular adaptation to hypoxia by activating oxygen-regulated genes such as vascular endothelial growth factor (VEGF) and erythropoietin. Sputum VEGF levels are reported to be decreased in COPD, despite hypoxia. Here we show that patients with COPD fail to induce HIF-1α and VEGF under hypoxic condition because of a reduction in histone deacetylase (HDAC) 7.Methods:Peripheral blood mononuclear cells (PBMCs) were obtained from patients with moderate to severe COPD (n = 21), smokers without COPD (n = 12), and nonsmokers (n = 15). PBMCs were exposed to hypoxia (1% oxygen, 5% CO2, and 94% N2) for 24 h, and HIF-1α and HDAC7 protein expression in nuclear extracts were determined by sodium dodecyl sulfate poly acrylamide gel electrophoresis (SDS-PAGE)/Western blotting.Results:HIF-1α was significantly induced by hypoxia in each group when compared with the normoxic condition (12-fold induction in nonsmokers, 24-fold induction in smokers without COPD, fourfold induction in COPD), but induction of HIF-1α under hypoxia was significantly lower in patients with COPD than in nonsmokers and smokers without COPD (P < .05 and P < .01, respectively). VEGF messenger RNA detected by quantitative real-time polymerase chain reaction was correlated with HIF-1α protein in nuclei (r = 0.79, P < .05), and HDAC7 protein expression was correlated with HIF-1α protein in nuclei (r = 0.46, P < .05). HDAC7 knockdown inhibited hypoxia-induced HIF-1α activity in U937 cells, and HIF-1α nuclear translocation and HIF-1α binding to the VEGF promoter in A549 cells.Conclusions:HDAC7 reduction in COPD causes a defect of HIF-1α induction response to hypoxia with impaired VEGF gene expression. This poor cellular adaptation might play a role in the pathogenesis of COPD.

VEGF and IL-18 in induced sputum of lung cancer patients

Cytokines are key players in the biological processes of malignant tumors and special interest has been focused on cytokines exerting tumor and anti-tumor properties, such as vascular endothelial growth factor (VEGF) and Interleukin-18 (IL-18). Aim of this study was to assess IL-18 and VEGF levels in induced sputum of lung cancer patients at diagnosis, and assess their possible association with the histological type of cancer, the stage and the overall patient survival. Seventy six patients with a diagnosis of lung cancer were recruited and were followed up for 48 months. Thirteen healthy smokers and 16 healthy non-smokers were used as control groups. VEGF and IL-18 were measured by ELISA in sputum supernatants at the time of diagnosis. Lung cancer patients had significantly higher baseline IL-18 and VEGF levels compared to healthy controls ( p < 0.001). No difference was found in IL-18 and VEGF levels between the various stages in non-small cell lung cancer (NSCLC) and between limited and extended small cell lung cancer (SCLC). However, the ratio of VEGF/IL-18 was significantly higher in NSCLC compared to SCLC patients ( p = 0.018). In extended SCLC overall survival was inversely associated with baseline sputum VEGF levels ( p = 0.034) and estimated mortality risk was 1.14 (95% CI 1.006–1.283) for an increase of 100 pg/ml in VEGF levels. Such association was not found regarding baseline IL-18 levels. VEGF levels in induced sputum may have a prognostic role in the survival of SCLC. The ratio VEGF/IL-18 in induced sputum differs between NSCLC and SCLC, indicating differences in angiogenesis mechanisms and/or immunological response in these two major histological types of lung cancer.

Vascular endothelial growth factor levels in induced sputum and emphysematous changes in smoking asthmatic patients

Although asthmatic patients frequently smoke cigarettes, the effect of smoking on asthmatic lungs has not been extensively studied. Vascular endothelial growth factor (VEGF) has been suggested to play a role in the pathogenesis of asthma and emphysema. To determine whether the level of airway VEGF might be related to emphysematous lung changes in asthmatic patients with a history of smoking. Pulmonary function tests and volumetric computed tomography (CT) of the lungs were performed in 10 ex-smoking and 15 nonsmoking asthmatic patients. Levels of VEGF were evaluated in the supernatants of induced sputum using an enzyme-linked immunosorbent assay method in these 25 asthmatic patients and in 10 healthy nonsmoking controls. Associations among sputum VEGF levels, emphysema indices on CT, and clinical variables were analyzed. Ex-smoking asthmatic patients showed a higher emphysema index on volumetric CT and a decreased mean forced expiratory volume in 1 second to forced vital capacity ratio compared with nonsmoking asthmatic patients. Sputum VEGF levels in asthmatic patients with a history of smoking were significantly lower than those in nonsmoking asthmatic patients but remained higher than those in control subjects. Furthermore, the emphysema index was significantly correlated with sputum VEGF levels in asthmatic patients. Lower VEGF levels in the airway might bea surrogate marker for emphysematous changes in the lungs, especially in asthmatic patients with a history of smoking.

Vascular endothelial growth factor overexpression in induced sputum of children with bronchial asthma

Vascular endothelial growth factor (VEGF) induces angiogenesis and increases vascular permeability participating in narrowing of the airway lumen that follows lung injury. We sought to investigate the expression of VEGF in induced sputum during and after recovery from acute episodes of bronchial asthma in children. Eighteen asthmatic children with acute attacks of varying severity were subjected to VEGF estimation by an enzymatic immunoassay in induced sputum. They were followed up till complete remission of symptoms and signs and were then retested. VEGF was also estimated in sputum induced from age 34 and sex-matched healthy children enrolled as a control group. The sputum VEGF levels during acute asthma [median = 71 ng/ml; mean (s.d.) = 114.6 (121.8) ng/ml] were significantly higher than the levels estimated during remission [median = 50 ng/ml; mean (s.d.) = 45.7 (24.2) ng/ml] and both were higher than the corresponding levels of the control group [median = 36 ng/ml; mean (s.d.) = 31.3 (17.2) ng/ml]. VEGF levels during asthmatic episodes correlated positively to the recovery levels (r = 0.6, p = 0.009). The patients' VEGF expression did not vary with asthma severity, serum total IgE concentration, peripheral blood eosinophil count, or erythrocyte sedimentation rate of patients. Children on corticosteroids inhalation therapy at enrollment had sputum VEGF levels that were comparable to those on other therapies. The increased expression of sputum VEGF in asthmatic children reinforces the concept that it might have a pathogenetic role in bronchial asthma and may represent a biomarker of airway inflammation.

Vascular remodeling is a feature of asthma and nonasthmatic eosinophilic bronchitis

Increased vascularity and expression of vascular endothelial growth factor (VEGF) are recognized features of the asthmatic airway. The association of vascular remodeling with airway hyperresponsiveness (AHR) is unclear. To assess vascular remodeling and sputum VEGF concentration in subjects with asthma, subjects with nonasthmatic eosinophilic bronchitis (EB), and healthy controls. In cohort 1, 19 patients with asthma (Global Initiative for Asthma [GINA] 1-2, n = 9; GINA 3-5, n = 10), 10 patients with EB, and 11 healthy matched controls were recruited. Expression of the endothelial marker EN4 was assessed in bronchial biopsy samples. Vessels were counted using the validated mean Chalkley count by a blind observer. For cohort 2, a second independent cohort of 31 patients with asthma (GINA 1-2, n = 11; GINA 3-5, n = 20), 14 patients with EB, and 15 matched controls was recruited. Induced sputum supernatant VEGF was measured by ELISA. The mean chalkley count was significantly greater in GINA 3-5 asthma (5.2 [0.4]) and EB (4.8 [0.3]) compared with controls (3.5 [0.5]) and demonstrated a significant inverse correlation with the postbronchodilator FEV(1)% predicted in patients with asthma (R(2) = 0.28; P = .02). Sputum VEGF concentration was also increased in GINA 3-5 asthma (2365 [1361-4110] pg/g) and EB (4699 [2818-7834] pg/g) compared with controls (1094 [676-1774] pg/g) and was inversely related to postbronchodilator FEV(1)% predicted in asthma (R(2) = 0.2; P = .01). Vascular remodeling is a feature of asthma, and EB and is inversely associated with the postbronchodilator FEV(1) in asthma, suggesting that vascular remodeling is associated with airflow obstruction but not AHR. Vascular remodeling is dissociated from AHR in asthma and associated with airflow limitation.

A Comparative Study of Two Angiogenic Factors: Vascular Endothelial Growth Factor and Angiogenin in Induced Sputum From Asthmatic Children in Acute Attack

Angiogenesis is a prerequisite for airway remodeling in bronchial asthma. Several factors may play important roles in inflammation and angiogenesis through effects on inflammatory cell infiltration or neovascularization. (1) To determine the levels of vascular endothelial growth factor (VEGF) and angiogenin in sputum supernatants of asthmatic children during the acute attack and 6 weeks after start of therapy; and (2) to correlate their levels with the degree of asthma severity. Twenty asthmatic children with acute attack (mean age, 9.6 +/- 3.5 years [+/- SD]) and 12 sex- and age-matched healthy control children were enrolled in the study. Sputum supernatants were collected for determination of VEGF and angiogenin levels. Serum samples were withdrawn for IgE measurement. The above tests were performed using an enzyme-linked immunosorbent assay. The FEV1 was measured using spirometry. VEGF, angiogenin, and FEV1 estimations were repeated for asthmatic children 6 weeks after start of therapy. During the acute attack, asthmatic children had significantly higher levels of VEGF and angiogenin than in healthy control children (p < 0.001). VEGF and angiogenin levels showed more elevation with increase in asthma severity (p < 0.001). A significant positive correlation existed between both angiogenic factors (r = 0.98, p < 0.001). A negative significant correlation was found between FEV1 percentage of predicted and both VEGF (r = -0.99, p < 0.001) and angiogenin (r = -0.97, p < 0.001). A nonsignificant correlation was found between serum IgE and sputum VEGF (r = 0.09, p > 0.05). Although there was a significant decrease in the levels of both VEGF and angiogenin after 6 weeks of treatment with corticosteroid inhalation therapy, the levels did not reach normal control levels (p < 0.001 and p < 0.05, respectively). Our results show that both VEGF and angiogenin levels were elevated in children with acute asthma. The study also suggests that increased severity of bronchial asthma in children is associated with the expression of both angiogenic factors, which are implicated in asthma pathogenesis. After 6 weeks of therapy, the levels of both angiogenic factors showed significant decrease.

Vascular endothelial growth factor overexpression in induced sputum of children with bronchial asthma

Vascular endothelial growth factor (VEGF) induces angiogenesis and increases vascular permeability participating in narrowing of the airway lumen that follows lung injury. We sought to investigate the expression of VEGF in induced sputum during and after recovery from acute episodes of bronchial asthma in children. Eighteen asthmatic children with acute attacks of varying severity were subjected to VEGF estimation by an enzymatic immunoassay in induced sputum. They were followed up till complete remission of symptoms and signs and were then retested. VEGF was also estimated in sputum induced from age 34 and sex-matched healthy children enrolled as a control group. The sputum VEGF levels during acute asthma [median = 71 ng/ml; mean (s.d.) = 114.6 (121.8) ng/ml] were significantly higher than the levels estimated during remission [median = 50 ng/ml; mean (s.d.) = 45.7 (24.2) ng/ml] and both were higher than the corresponding levels of the control group [median = 36 ng/ml; mean (s.d.) = 31.3 (17.2) ng/ml]. VEGF levels during asthmatic episodes correlated positively to the recovery levels (r = 0.6, p = 0.009). The patients' VEGF expression did not vary with asthma severity, serum total IgE concentration, peripheral blood eosinophil count, or erythrocyte sedimentation rate of patients. Children on corticosteroids inhalation therapy at enrollment had sputum VEGF levels that were comparable to those on other therapies. The increased expression of sputum VEGF in asthmatic children reinforces the concept that it might have a pathogenetic role in bronchial asthma and may represent a biomarker of airway inflammation.

Acute and chronic changes of vascular endothelial growth factor (VEGF) in induced sputum of toluene diisocyanate (TDI)-induced asthma patients.

Vascular endothelial growth factor (VEGF) is a multi-functional cytokine involved in inflammation, repair and angiogenesis in asthmatic airway. This study aimed to evaluate the role of VEGF in immediate bronchoconstriction induced by TDI inhalation, and in chronic TDI-asthma patients. 11 newly diagnosed TDI-asthma patients (group I), 12 chronic TDI-asthma patients with persistent asthma symptoms followed for >4 yr and 15 unexposed healthy controls were enrolled. In group I, induced sputum and serum were collected before and 7 hr after placebo- and TDI-bronchoprovocation test (BPT). In group II, induced sputum and serum were collected every 2 yr. VEGF levels were measured by ELISA. There were no significant differences in sputum and serum VEGF levels between patients and controls. Before and after placebo- and TDI-BPT, no significant changes were noted in sputum and serum VEGF levels of group I. In group II patients, sputum VEGF showed variable changes at 1-yr, then decreased significantly at 2-yr (p<0.05), while serum VEGF showed variable changes at 2-yr, which decreased significantly at 4-yr (p<0.05). These results suggest that VEGF may play a minor role in immediate bronchoconstriction after TDI-BPT. In chronic TDI-asthma, VEGF may be involved to 2 yr after the diagnosis and the contribution may decrease after then.

Possible effects of vascular endothelial growth factor in the pathogenesis of chronic obstructive pulmonary disease

Purpose Expression of vascular endothelial growth factor (VEGF) is reduced in the lungs of patients with emphysema. We examined whether VEGF levels in sputum differed in patients with emphysema, bronchitis, or asthma, as compared with controls. Methods Fifty-nine patients with chronic obstructive pulmonary disease (COPD) (25 with emphysema, 19 with chronic bronchitis, and 15 with a mixed type), 20 patients with bronchial asthma, and 11 normal controls were included in the study. The concentration of VEGF in induced sputum and the correlations between VEGF levels and pulmonary function were examined. Results The mean (± SD) concentration of VEGF in induced sputum was significantly higher in patients with asthma (6440 ± 1820 pg/mL, P <0.0001) or bronchitis (4120 ± 1100 pg/mL, P <0.0001) than in normal controls (1860 ± 1220 pg/mL), but significantly lower in patients with emphysema (500 ± 300 pg/mL, P = 0.03). The concentration of VEGF in sputum from patients with bronchitis correlated inversely with forced expiratory volume in 1 second ( r = −0.87; P = 0.0002); in contrast, there was a positive correlation between these two measurements in patients with emphysema ( r = 0.82; P <0.0001). In addition, sputum VEGF concentrations correlated with the diffusing capacity of carbon monoxide in patients with emphysema ( r = 0.87; P <0.0001), but not in those with bronchitis ( r = −0.22; P = 0.36). Conclusion In patients with bronchitis, increased levels of VEGF in induced sputum were associated with airflow limitation. In contrast, decreased levels of VEGF were associated with airflow limitation and alveolar destruction in patients with emphysema. Thus, our findings suggest that VEGF may affect the pathogenesis of these two common types of COPD.