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Increased expression of placenta growth factor in COPD.

Cheng SL, Wang HC, Yu CJ, Yang PC - Thorax (2008)

Bottom Line: Continuous concomitant treatment with PlGF, TNF-alpha and IL-8 stimulation reduced VEGF expression and induced cell death.This phenomenon was suppressed by VEGF receptor inhibitor (CBO-P11).Concomitant treatment with PlGF, TNF-alpha and IL-8 causes detrimental effects on airway epithelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan.

ABSTRACT

Background: Vascular endothelial growth factor (VEGF) and its receptor may have an important role in the pathogenesis of emphysema. The effect of another angiogenic factor, placenta growth factor (PlGF), in chronic obstructive pulmonary disease (COPD) is unknown.

Methods: The serum levels of VEGF and PlGF in patients with COPD (n = 184), smokers (n = 212) and non-smokers (n = 159) and the bronchoalveolar lavage (BAL) fluid levels of VEGF and PlGF in another group (20 patients with COPD, 18 controls) were measured. In vitro cell culture experiments were performed to investigate the effect of PlGF on VEGF.

Results: The mean (SE) serum levels of PlGF were significantly higher in patients with COPD than in controls (27.1 (7.4) pg/ml vs 12.3 (5.1) pg/ml in smokers and 10.8 (6.3) pg/ml in non-smokers, p = 0.005). The levels of PlGF in BAL fluid were also significantly higher in patients with COPD than in controls (45.7 (12.3) pg/ml vs 23.9 (7.6) pg/ml, p = 0.005), associated with an increase in the cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8). In patients with COPD the levels of PlGF correlated inversely with forced expiratory volume in 1 s (FEV(1)) in serum (r = -0.59, p = 0.002) and in BAL fluid (r = -0.51, p = 0.001). While the serum levels of VEGF were the same in patients with COPD and controls, the BAL fluid levels were significantly lower in patients with COPD than in controls (127.5 (30.1) pg/ml vs 237.8 (36.1) pg/ml, p = 0.002). In cultured bronchial epithelial cells, proinflammatory cytokines induced an increase in the protein expression of both PlGF and VEGF. Continuous concomitant treatment with PlGF, TNF-alpha and IL-8 stimulation reduced VEGF expression and induced cell death. This phenomenon was suppressed by VEGF receptor inhibitor (CBO-P11).

Conclusions: The serum and BAL fluid levels of PlGF are increased in patients with COPD and are inversely correlated with FEV(1). Concomitant treatment with PlGF, TNF-alpha and IL-8 causes detrimental effects on airway epithelial cells. These data suggest that bronchial epithelial cells can express PlGF, which may contribute to the pathogenesis of COPD.

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(A) Effect of persistent stimulation with a combination of PlGF, TNF-α, IL-8 and CBO-P11 1 μM/l on VEGF expression in S-cells. Western blotting and ELISA analysis show VEGF expression from day 1 to 14. There was no statistically significant difference during this period (*p = 0.52); C, control at day 14. Error bars are presented as standard deviations. (B) Percentage S-cell viability following stimulation with a combination of PlGF, TNF-α, IL-8 and CBO-P11 measured by trypan blue exclusion. The percentage of cell deaths was not significantly increased after 14 days of exposure (†p = 0.61 vs day 7). Error bars are presented as standard deviations. (C) Caspase-3 activity assay for S-cells after stimulation with a combination of PlGF, TNF-α, IL-8 and CBO-P11. The signal was analysed after subtracting the appropriate number of cells/buffer controls. Caspase-3 activity did not increase after 14 days of exposure (†p = 0.37 vs day 7). Error bars are presented as standard deviations. VEGF, vascular endothelial growth factor; PlGF, placenta growth factor; TNF-α, tumour necrosis factor-α; IL-8, interleukin-8; RFU, relative signal.
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THX-63-06-0500-f04: (A) Effect of persistent stimulation with a combination of PlGF, TNF-α, IL-8 and CBO-P11 1 μM/l on VEGF expression in S-cells. Western blotting and ELISA analysis show VEGF expression from day 1 to 14. There was no statistically significant difference during this period (*p = 0.52); C, control at day 14. Error bars are presented as standard deviations. (B) Percentage S-cell viability following stimulation with a combination of PlGF, TNF-α, IL-8 and CBO-P11 measured by trypan blue exclusion. The percentage of cell deaths was not significantly increased after 14 days of exposure (†p = 0.61 vs day 7). Error bars are presented as standard deviations. (C) Caspase-3 activity assay for S-cells after stimulation with a combination of PlGF, TNF-α, IL-8 and CBO-P11. The signal was analysed after subtracting the appropriate number of cells/buffer controls. Caspase-3 activity did not increase after 14 days of exposure (†p = 0.37 vs day 7). Error bars are presented as standard deviations. VEGF, vascular endothelial growth factor; PlGF, placenta growth factor; TNF-α, tumour necrosis factor-α; IL-8, interleukin-8; RFU, relative signal.

Mentions: The expression of VEGF after 14 days of treatment with PlGF, TNF-α or IL-8 using concentrations close to those in the BAL fluid of patients with COPD (PlGF 50 pg/ml, TNF-α 200 pg/ml and IL-8 200 pg/ml) is shown in fig 3A. With TNF-α or IL-8 stimulation alone, the expression of VEGF gradually increased during the initial 7 days and then decreased after 10–14 days of treatment. The same finding was noted after concomitant treatment with TNF-α (200 pg/ml) and IL-8 (200 pg/ml) for 10 days (fig 3B). After 10 days exposure to 50 pg/ml PlGF alone the level of VEGF decreased (fig 3A), but the expression of VEGF was significantly reduced after 10 days of concomitant treatment with PlGF (50 pg/ml), TNF-α (200 pg/ml) and IL-8 (200 pg/ml) (fig 3C). A cell viability test showed a significant increase in the percentage of dead cells after cytokine exposure for 14 days (fig 3D). Apoptosis analysis with the caspase-3 activity assay showed a considerable increase in apoptotic cells during the 14 days of stimulation (fig 3E). The addition of VEGFR inhibitor (CBO-P11) in a concentration that mainly blocked VEGFR1 binding throughout the 14-day experimental period to the mixture of TNF-α, IL-8 and PlGF avoided the suppression of VEGF expression (fig 4A), maintained S-cell viability (fig 4B) and prevented apoptosis (fig 4C). CBO-P11 prevented the suppression of VEGF expression in a dose-dependent manner (fig 5A) with an EC50 of 415 nM (fig 5B). The caspase-3 activity was also ameliorated with increasing doses of CBO-P11 (fig 5C).


Increased expression of placenta growth factor in COPD.

Cheng SL, Wang HC, Yu CJ, Yang PC - Thorax (2008)

(A) Effect of persistent stimulation with a combination of PlGF, TNF-α, IL-8 and CBO-P11 1 μM/l on VEGF expression in S-cells. Western blotting and ELISA analysis show VEGF expression from day 1 to 14. There was no statistically significant difference during this period (*p = 0.52); C, control at day 14. Error bars are presented as standard deviations. (B) Percentage S-cell viability following stimulation with a combination of PlGF, TNF-α, IL-8 and CBO-P11 measured by trypan blue exclusion. The percentage of cell deaths was not significantly increased after 14 days of exposure (†p = 0.61 vs day 7). Error bars are presented as standard deviations. (C) Caspase-3 activity assay for S-cells after stimulation with a combination of PlGF, TNF-α, IL-8 and CBO-P11. The signal was analysed after subtracting the appropriate number of cells/buffer controls. Caspase-3 activity did not increase after 14 days of exposure (†p = 0.37 vs day 7). Error bars are presented as standard deviations. VEGF, vascular endothelial growth factor; PlGF, placenta growth factor; TNF-α, tumour necrosis factor-α; IL-8, interleukin-8; RFU, relative signal.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2571977&req=5

THX-63-06-0500-f04: (A) Effect of persistent stimulation with a combination of PlGF, TNF-α, IL-8 and CBO-P11 1 μM/l on VEGF expression in S-cells. Western blotting and ELISA analysis show VEGF expression from day 1 to 14. There was no statistically significant difference during this period (*p = 0.52); C, control at day 14. Error bars are presented as standard deviations. (B) Percentage S-cell viability following stimulation with a combination of PlGF, TNF-α, IL-8 and CBO-P11 measured by trypan blue exclusion. The percentage of cell deaths was not significantly increased after 14 days of exposure (†p = 0.61 vs day 7). Error bars are presented as standard deviations. (C) Caspase-3 activity assay for S-cells after stimulation with a combination of PlGF, TNF-α, IL-8 and CBO-P11. The signal was analysed after subtracting the appropriate number of cells/buffer controls. Caspase-3 activity did not increase after 14 days of exposure (†p = 0.37 vs day 7). Error bars are presented as standard deviations. VEGF, vascular endothelial growth factor; PlGF, placenta growth factor; TNF-α, tumour necrosis factor-α; IL-8, interleukin-8; RFU, relative signal.
Mentions: The expression of VEGF after 14 days of treatment with PlGF, TNF-α or IL-8 using concentrations close to those in the BAL fluid of patients with COPD (PlGF 50 pg/ml, TNF-α 200 pg/ml and IL-8 200 pg/ml) is shown in fig 3A. With TNF-α or IL-8 stimulation alone, the expression of VEGF gradually increased during the initial 7 days and then decreased after 10–14 days of treatment. The same finding was noted after concomitant treatment with TNF-α (200 pg/ml) and IL-8 (200 pg/ml) for 10 days (fig 3B). After 10 days exposure to 50 pg/ml PlGF alone the level of VEGF decreased (fig 3A), but the expression of VEGF was significantly reduced after 10 days of concomitant treatment with PlGF (50 pg/ml), TNF-α (200 pg/ml) and IL-8 (200 pg/ml) (fig 3C). A cell viability test showed a significant increase in the percentage of dead cells after cytokine exposure for 14 days (fig 3D). Apoptosis analysis with the caspase-3 activity assay showed a considerable increase in apoptotic cells during the 14 days of stimulation (fig 3E). The addition of VEGFR inhibitor (CBO-P11) in a concentration that mainly blocked VEGFR1 binding throughout the 14-day experimental period to the mixture of TNF-α, IL-8 and PlGF avoided the suppression of VEGF expression (fig 4A), maintained S-cell viability (fig 4B) and prevented apoptosis (fig 4C). CBO-P11 prevented the suppression of VEGF expression in a dose-dependent manner (fig 5A) with an EC50 of 415 nM (fig 5B). The caspase-3 activity was also ameliorated with increasing doses of CBO-P11 (fig 5C).

Bottom Line: Continuous concomitant treatment with PlGF, TNF-alpha and IL-8 stimulation reduced VEGF expression and induced cell death.This phenomenon was suppressed by VEGF receptor inhibitor (CBO-P11).Concomitant treatment with PlGF, TNF-alpha and IL-8 causes detrimental effects on airway epithelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan.

ABSTRACT

Background: Vascular endothelial growth factor (VEGF) and its receptor may have an important role in the pathogenesis of emphysema. The effect of another angiogenic factor, placenta growth factor (PlGF), in chronic obstructive pulmonary disease (COPD) is unknown.

Methods: The serum levels of VEGF and PlGF in patients with COPD (n = 184), smokers (n = 212) and non-smokers (n = 159) and the bronchoalveolar lavage (BAL) fluid levels of VEGF and PlGF in another group (20 patients with COPD, 18 controls) were measured. In vitro cell culture experiments were performed to investigate the effect of PlGF on VEGF.

Results: The mean (SE) serum levels of PlGF were significantly higher in patients with COPD than in controls (27.1 (7.4) pg/ml vs 12.3 (5.1) pg/ml in smokers and 10.8 (6.3) pg/ml in non-smokers, p = 0.005). The levels of PlGF in BAL fluid were also significantly higher in patients with COPD than in controls (45.7 (12.3) pg/ml vs 23.9 (7.6) pg/ml, p = 0.005), associated with an increase in the cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8). In patients with COPD the levels of PlGF correlated inversely with forced expiratory volume in 1 s (FEV(1)) in serum (r = -0.59, p = 0.002) and in BAL fluid (r = -0.51, p = 0.001). While the serum levels of VEGF were the same in patients with COPD and controls, the BAL fluid levels were significantly lower in patients with COPD than in controls (127.5 (30.1) pg/ml vs 237.8 (36.1) pg/ml, p = 0.002). In cultured bronchial epithelial cells, proinflammatory cytokines induced an increase in the protein expression of both PlGF and VEGF. Continuous concomitant treatment with PlGF, TNF-alpha and IL-8 stimulation reduced VEGF expression and induced cell death. This phenomenon was suppressed by VEGF receptor inhibitor (CBO-P11).

Conclusions: The serum and BAL fluid levels of PlGF are increased in patients with COPD and are inversely correlated with FEV(1). Concomitant treatment with PlGF, TNF-alpha and IL-8 causes detrimental effects on airway epithelial cells. These data suggest that bronchial epithelial cells can express PlGF, which may contribute to the pathogenesis of COPD.

Show MeSH
Related in: MedlinePlus