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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 31  |  Issue : 2  |  Page : 695-702

Assessment of circulating vascular endothelial growth factor in patients with stable and exacerbated chronic obstructive pulmonary disease


1 Department of Chest, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
2 Department of Medical Biochemistry, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
3 Department of Chest, Al-Mahalla Chest Hospital, Al-Mahalla, Egypt

Date of Submission27-Sep-2016
Date of Acceptance02-Dec-2016
Date of Web Publication27-Aug-2018

Correspondence Address:
Dalia I El-Gammal
Al-Mahalla Chest Hospital, Al-Mahalla
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.239736

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  Abstract 


Objective
This study aimed to evaluate the diagnostic value of serum vascular endothelial growth factor (VEGF) assessment during stable and acute exacerbations of chronic obstructive pulmonary disease (COPD).
Background
VEGF is a cytokine that has potent angiogenic and vascular permeability-enhancing activities. VEGF serum level was found to increase in a number of inflammatory disorders.
Patient and methods
This study was carried out in the Chest and Medical Biochemistry Departments, Faculty of Medicine, Menoufia University and El-Mahalla Chest Hospital in the period from July 2015 to March 2016. It included 75 patients, with a mean age of 54.7 ± 7.55 years. The patients were subjected to clinical examination and standard spirometric measures including percentage of predicted forced vital capacity, percentage of predicted forced expiratory volume in the first second, and forced expiratory volume in the first second/forced vital capacity ratio. Measurement of VEGF serum levels was done in patients with acute exacerbations of COPD on the first day of hospitalization, whereas for patients with stable COPD and for the healthy controls, the sample was taken on the same day of the spirometric maneuver.
Results
VEGF level was significantly elevated in patients with stable chronic obstructive pulmonary disease (COPD) compared with controls and also was significantly higher in patients with acute exacerbations of COPD compared with patients with stable COPD.
Conclusion
VEGF is significantly elevated in patients with acute exacerbations of COPD and is proportional to the severity of stable COPD. Therefore, it can be used as a biomarker for COPD.

Keywords: chronic obstructive pulmonary disease, pulmonary, vascular endothelial growth factor


How to cite this article:
Azab NY, El-Habashy MM, El-Shafie MK, El-Gammal DI. Assessment of circulating vascular endothelial growth factor in patients with stable and exacerbated chronic obstructive pulmonary disease. Menoufia Med J 2018;31:695-702

How to cite this URL:
Azab NY, El-Habashy MM, El-Shafie MK, El-Gammal DI. Assessment of circulating vascular endothelial growth factor in patients with stable and exacerbated chronic obstructive pulmonary disease. Menoufia Med J [serial online] 2018 [cited 2018 Nov 20];31:695-702. Available from: http://www.mmj.eg.net/text.asp?2018/31/2/695/239736




  Introduction Top


Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable disease, characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases.

COPD produces significant systemic consequences, which can be detected clinically and appear to be associated with the presence of systemic inflammatory markers such as vascular endothelial growth factor (VEGF) [1].

VEGF, a soluble heparin-binding glycoprotein, is a cytokine with potent angiogenic properties, enhancing vascular permeability and modulating thrombogenicity [2]. VEGF further serves as an endothelial cell survival factor, protecting endothelial cells against apoptosis and delaying endothelial cell senescence [3]. VEGF has been measured in the peripheral circulation as a biomarker of neovascularization and/or vascular remodelling. Several studies have reported increased circulating VEGF levels in conditions in which tissue hypoxia and/or inflammation are critical [4]. Furthermore, there is accumulating evidence that circulating VEGF levels have prognostic significance in cardiovascular disease (CVD) [5], which could provide a mechanism to link between inflammation and promotion of CVD. Both hypoxia and inflammation are also relevant to COPD [6].


  Patients and Methods Top


Patients

This study was carried out in the Chest and Medical Biochemistry Departments, Faculty of Medicine, Menoufia University and El-Mahalla Chest Hospitals in the period from July 2015 to March 2016.

The study included 75 patients randomly selected and divided into three groups as follows:

Group A: It included 25 nonsmoking healthy individuals as a control group.

Group B: It included 25 patients with stable COPD who were followed up at the chest out patient's clinic of El-Mahalla Chest Hospital with no history of exacerbations in the past 3 months.

Group C: It included 25 patients with COPD admitted to the chest ward with acute exacerbation.

Inclusion criteria

Patients were defined as having COPD according to GOLD criteria 2013. A postbronchodilator forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio of less than 0.70 confirms the presence of airflow limitation, also reversibility of airway obstruction and improvement in flow rates are less than 12% of absolute value of FEV1. Acute exacerbation was defined as a sustained worsening of the patient's condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD.

Exclusion criteria

  1. FEV1/FVC of more than 70%
  2. Patients with any other chest disease
  3. Patients with any other systemic disease, as chronic liver disease, renal disease, rheumatoid arthritis, and heart failure
  4. Patients with respiratory failure.


Patients had a mean age of 54.7 ± 7.55 years. The study included 25 patients with stable COPD, 25 patients with acute exacerbations of COPD, and 25 normal healthy individuals. An informed consent form was taken from all the patients and controls, and they were informed about all the investigations that would be done.


  Methods Top


All patients are subjected to the following:

  1. History taking.
  2. Clinical examination
  3. Radiographic study


    1. Plain chest radiography posteroanterior and lateral views
    2. Computerized tomography for chest if indicated


  4. Standard spirometric measures including FVC% of predicted, FEV1% of predicted, and FEV1/FVC ratio
  5. Arterial blood gases when needed
  6. Laboratory investigations:


    1. Routine laboratory investigations


      1. Complete blood count
      2. Erythrocyte sedimentation rate
      3. Liver function tests
      4. Kidney function tests


    2. Quantitative determination of VEGF concentrations in serum using enzyme-linked immunosorbent assay (R & D Systems, Abington, UK) in duplicate, according to the protocol recommended by the manufacturer.


Sample collection and storage

Overall, 3 ml of venous blood from the patients was taken under aseptic condition; for the hospitalized patients with acute exacerbations of COPD, the blood sample was taken on the first day of hospitalization, whereas for the patients with stable COPD and for the healthy controls, the sample was taken at the same day of the spirometric maneuver. Some samples were excluded because of hemolysis and jaundice.

Serum separator tubes were used.

Samples were allowed to clot for 30 min before centrifugation for 15 min at 1000g.

Sera were removed immediately and samples were stored at −20°C or less.

Sample was separated and aliquoted in 500-μl fraction each and stored at −80°C until assay. VEGF concentration in sera was measured using a commercial Human VEGF ELISA kit (R & D Systems).

Test principle

Quantitative sandwich enzyme immunoassay was used, and the system uses a solid-phase monoclonal antibodies and an enzyme-linked polyclonal antibody raised against recombinant human VEGF that recognizes soluble isoforms (VEGF121 and VEGF165). The assay is sensitive to 9 pg/ml, and the dose does not react with platelet-derived growth factor or other homologous cytokines.

Test procedure

For each sample, 100-μl serum was used, and VEGF for each sample was measured in duplicate. The test was done following manufacturer's instructions. Briefly, serum samples of standards and control were pipetted into the wells precoated with Abs specific for VEGF. After first incubation at room temperature followed by wash, a biotinylated monoclonal Abs specific for VEGF was added, and the plate was reincubated. After wash, streptavidin–horseradish peroxidase enzyme was added, and the plate was incubated again and then washed. Lastly, a substrate was added to produce color, and the intensity of this color was directly proportional to the concentration of VEGF in the original samples. Optical density was read at 450 nm with microtiter plate reader, and VEGF concentrations were estimated from standard curve and reported in pg/ml.

Statistical analysis

Comparisons where done among 25 patients with stable COPD, 25 patients with acute exacerbations of COPD, and 25 normal healthy subjects. The level of significance was at 0.05. Odds ratio was also calculated. To clarify the validity of serum VEGF test in patients with COPD, the sensitivity and specificity of the test were measured.


  Results Top


Demographic characteristics of individuals and patients are outlined in [Table 1]. No significant difference was found between patients with COPD and controls regarding age, sex, and BMI. Also, there was no significant difference between patients with stable COPD and those with acute exacerbation of COPD regarding smoking index (P > 0.05)
Table 1: Statistical comparison between patients with chronic obstructive pulmonary disease and controls regarding demographic data and smoking index (n=25)

Click here to view


[Table 2] and [Figure 1] show that serum VEGF was significantly elevated in patients with COPD (571 ± 134.1 pg/ml) compared with control individuals (298.3 ± 38.2 pg/ml) (P ≤ 0.001).
Table 2: Comparison between patients with chronic obstructive pulmonary disease and the control group regarding serum vascular endothelial growth factor

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Figure 1: Comparison between the three studied groups regarding serum level of vascular endothelial growth factor.

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[Table 3] and [Figure 1] show that serum VEGF was significantly elevated in patients with stable COPD (444.5 ± 36.6 pg/ml) compared with control individuals (298.3 ± 38.2 pgl ml) (P < 0.01).
Table 3: Comparison between stable chronic obstructive pulmonary disease patients and controls regarding serum level of vascular endothelial growth factor

Click here to view


[Table 4] and [Figure 2] show that VEGF was significantly elevated in patients with acute exacerbations of COPD (698.64 ± 1.7 pg/ml) compared with patients with stable COPD (444.5 ± 36.6 pg/ml) (P ≤ 0.001).
Table 4: Comparison between both subgroups of chronic obstructive pulmonary disease regarding serum vascular endothelial growth factor level

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Figure 2: Specificity, sensitivity, positive predictive value, negative predicted value, and P value of vascular endothelial growth factor. ROC, receiver operating characteristic.

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[Table 5] shows that VEGF had a sensitivity of 88%, a specificity of 98%, a positive predicted value of 93.6, and a negative predicted value of 78.5, with statistically significant value (P < 0.05).
Table 5: Specificity, sensitivity, positive predictive value, negative predicted value, and P value of vascular endothelial growth factor level

Click here to view



  Discussion Top


The mean age of the patients with COPD was 54.7 ± 7.55 years, and the mean age of the controls was 52.12 ± 4.9 years. There was no statistically significant difference between patients and controls regarding their age P > 0.05).

The mean age of patients with stable COPD was 53.5 ± 6.9 years and that of patients with exacerbations of COPD was 55.9 ± 8.2 years. There was no statistically significant difference between them (P > 0.05).

When evaluating the age as a risk factor for COPD, it is important to evaluate their spirometric criteria. A fixed ratio for the definition of airway obstruction (FEV1/FVC < 0.7) will overestimate COPD in elderly and underestimate COPD among young adults [7].

The link between aging and the pathogenesis of COPD is strongly supported by numerous studies [8],[9]. During aging, pulmonary function progressively deteriorates and pulmonary inflammation increases, accompanied by structural changes, which are described as senile emphysema. Environmental gases, such as cigarette smoke or other pollutants, may accelerate the aging of lung or worsen aging-related events in lung by defective resolution of inflammation, for example, by reducing antiaging molecule, and this consequently induces accelerated progression of COPD [10],[11].

In the present study, pack-year index showed a statistically insignificant difference in patients with COPD in comparison with the control group.

Guerr et al. [12] found that men in the lowest BMI percentile at baseline were almost three times more likely to be diagnosed as having COPD during the follow-up period than men in the highest percentile.

In another study, Sahebjami et al. [13] found that underweight patients with COPD were found to have lower carbon monoxide diffusing capacity and higher dyspnea scores than normal weight patients with dyspnea.

El-Badrawy et al. [14] found that the mean values of BMI were slightly higher in patients with COPD than in healthy individuals.

In this work, all patients were males. COPD is a male-dominant disease; the high prevalence in males is because if the higher prevalence of smoking in this sex, and also males are more exposed to smoking than females [15]. Again, more frequent occupational exposures of significance are present in men [16].

In this study, there was no statistically significant difference between patients with stable COPD and patients with exacerbations of COPD regarding their pack-year index (P > 0.05).

Many epidemiological studies have found that cigarette smoking is by far the most important risk factor for COPD. It is also known that total pack-year of smoking are predictive of COPD mortality [17],[18].

According to Lindstrom et al. [19], there is a relation between the increased risk of lung toxicity of long-term smoking with the time and amount of smoking. Also, Lindberg and colleagues found a high cumulative incidence of COPD after 10 years of smoking. This emphasizes the importance of early smoking cessation in the reduction of incidence of COPD [20].

Cigarette smoking causes 85% of COPD cases, and smokers are 10 times more likely to develop COPD than nonsmokers. Cigarette smoking irritates the airways, and mucus production increases in response to cigarette smoke. Cigarette smoking also damages the cilia that remove debris from the lungs [21].

The selection of the studied patients with nonsignificant differences in age and BMI, and of the same sex eliminates any effect of these factors on the results.

In the present study, there was a highly statistically significant difference between patients and controls regarding pulmonary function tests.

Comparison between patients with stable COPD and controls showed a highly statistically significant difference regarding FVC% of predicted, FEV1% of predicted, and FEV1/FVC ratio (P < 0.001).

Another comparison between patients with stable COPD and patients with acute exacerbations of COPD showed that there was a statistically significant difference regarding FVC% of predicted and FEV1/FVC ratio (P < 0.05) and a highly statistically significant difference regarding FEV1% of predicted (P < 0.001).

A third comparison between controls and patients with acute exacerbations, showed that there was a highly statistically significant difference regarding FVC% of predicted, FEV1% of predicted, and FEV1/FVC ratio (P < 0.001).

The decline shown in FEV1% predicted in this study was because of inflammatory changes occurring at different levels in the lungs in addition to mucous hypersecretion.

COPD is associated with chronic inflammation in the airways and lung parenchyma [22],[23].

Acute exacerbations of COPD are associated with exaggerated inflammatory changes showing increased numbers of eosinophils, neutrophils, CD-3 lymphocytes, and tumor necrosis factor-α (TNF-α)-positive cells in bronchial biopsies compared with COPD examined under conditions of clinical stability [24]. Also, acute exacerbations of COPD demonstrate elevated markers of airway neutrophilic inflammation relative to their clinically stable state. Sputum levels of interleukin-8 and TNF-α increased significantly in patients at the time of exacerbations, and then fell again back to baseline levels 1 month later [25].

However, even stable COPD represents a continuous state of inflammation, although not appreciated by the patient, in which there is increased numbers of neutrophils and macrophages in the sputum and broncho-alveolar lavage fluid relative to normal individuals [26].

Also, induced sputum from patients with stable COPD have revealed elevated levels of granulocyte activation markers myeloperoxidase (MPO), human neutrophil lipocalin [27] and neutrophil chemoattractants interleukin-8 and TNF-α [28].

Cirillo et al. [29] have shown that moderate to severe COPD is strongly associated with systemic low-grade inflammation.

The extent of inflammation, fibrosis, and luminal exudates in small airways is correlated with the reduction in FEV1% of predicted and FEV1/FVC ratio, and probably with the accelerated decline in FEV1% of predicted, characteristic of COPD [30].

In the present study, serum VEGF levels were significantly elevated in stable COPD group compared with the control group with the highest levels in patients with acute exacerbations.

Patients with stable COPD had significantly elevated levels of VEGF (444.5 ± 36.6 pg/ml) compared with controls (298.3 ± 38.2 pg/ml) (P ≤ 0.001), because there is minimal persistent systemic inflammation [25].

Nahed et al. [31] found that serum levels of VEGF were highly significantly increased in patients with COPD (552.2 ± 127.3 pg/ml) compared with healthy controls (192.9 ± 55.4 pg/ml).

In another study, Kierszniewska-Stepien et al. [32] found that serum VEGF levels were significantly elevated in patients with mild stable COPD (665.31 ± 102.20 pg/ml) compared with the healthy controls (318.94 ± 51.40 g/ml).

Aaron et al. [33] assessed serum and induced sputum VEGF in 42 patients: 21 with stable COPD and 21 controls.

VEGF levels were found to be significantly higher in patients with COPD compared with controls.

However, they concluded that levels of many serum and sputum biomarkers cannot be reliably ascertained based on single measurements. Multiple measurements over time can give a more reliable and precise estimate of the inflammatory burden in patients with clinically stable COPD [33].

By comparing both subgroups of COPD, VEGF was significantly elevated in patients with acute exacerbations of COPD (698.6 ± 41.7 pg/ml) compared with patients with stable COPD (444.5 ± 36.6 pg/ml) (P ≤ 0.001). Because VEGF also increases as a part of the inflammatory response, it can be used as a marker of exacerbations.

Valipour et al. [34] found that serum VEGF levels were significantly elevated in both AECOPD (457–883 pg/ml) and stable COPD (151–310 pg/ml) groups compared with the healthy controls (134–363 pg/ml) with the highest levels in the AECOPD group.

They observed that recovery from an exacerbation resulted in a decrease in circulating VEGF levels and systemic inflammatory markers in patients with COPD [34]. Similar results have been obtained by Mc Colley et al. [35].

These results matched with Pavlisa et al. [36] who showed that serum VEGF levels were significantly higher in patients experiencing acute exacerbations of COPD (the mean value was 1.089.16 ± 1.128.03 pg/ml), compared with patients with stable COPD (the mean value was 197.68 ± 178.06 pg/ml) and controls (the mean value was 257.69 ± 170.4 pg/ml).

Opposing the results of the current of study, Hurst et al. [37] did not observe a significant difference in median plasma VEGF levels between baseline (0.01 pg/ml) and exacerbations (0.01 pg/ml).

The comparison between different severities of stable COPD regarding serum VEGF, showed no statistically significant difference between them (P > 0.05).

In this study, at a cut-off value of 224 pg/ml, VEGF had a sensitivity of 88%, a specificity of 98%, positive predicted value of 93.6% and negative predicted value of 78.5%.

VEGF production can be induced in cells that are not receiving enough oxygen [38]. When a cell is deficient of oxygen, it produces hypoxia-inducible factor, which is a transcription factor. Hypoxia-inducible factor stimulates the release of VEGF that binds to VEGF receptors on endothelial cells, triggering a tyrosine kinase pathway, leading to angiogenesis [39].

Also, VEGF may be released in response to inflammatory stimuli [40]. Mittermayer et al. [41] observed a significant increase in circulating VEGF levels in healthy volunteers after experimentally induced systemic inflammation. There is cumulating evidence that neutrophils contribute to circulating VEGF [42],[43].

Valipour et al. [34] observed a strong relationship between levels of VEGF and peripheral blood neutrophil count, which may support a role for neutrophils in blood-borne VEGF. In disease conditions, the amount of neutrophil-derived VEGF may increase further. Neutrophils may secrete VEGF in response to acute inflammatory stimuli associated with viral [44] and bacterial [45] infections, which are frequently associated with exacerbations of COPD [46].

Valipour et al. [34] found that there is no significant difference in serum level VEGF between patients with stable, moderate to severe COPD and healthy controls.

However, Nahed et al. [31] found a significant difference between the levels of VEGF in patients with different COPD severities.

Also, Kierszniewska-Stepie et al. [32] found that serum VEGF concentration in patients with mild COPD correlated negatively with FEV1.

Raidl and colleagues reported that VEGF production was dependent on phosphorylation of ERK-1/2 and p38-MAPK, there were no differences between nonsmokers, smokers without airflow limitation, and smokers with COPD in this respect. Dexamethasone reduced TNF-α-induced phosphorylation of ERK-1/2 and prevented TNF-α-induced VEGF generation without differences between nonsmokers, smokers with COPD and smokers without COPD [47].

However, Ito [48] stated that the basal and TNF-α-induced acetylation status of the VEGF-promoter was increased in smokers with COPD compared with smokers without airflow limitation and nonsmokers.


  Conclusion Top


Serum VEGF is significantly elevated in patients with COPD, so it may be used as a biomarker for COPD.

Serum VEGF is significantly elevated during acute exacerbations of COPD, so it may be used as a biomarker for COPD exacerbation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

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