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(Chest. 2000;118:1747-1753.)
© 2000 American College of Chest Physicians

Vascular Endothelial Growth Factor Level Correlates With Transforming Growth Factor-ß Isoform Levels in Pleural Effusions*

Dong-sheng Cheng, MD; Y. C. Gary Lee, MBChB; Jeffrey T. Rogers, RRT; Elizabeth A. Perkett, MD; J. Philip Moyers, MD; R. Michael Rodriguez, MD and Richard W. Light, MD, FCCP

* From the Department of Pulmonary Medicine (Drs. Cheng, Lee, Moyers, Rodriguez and Mr. Rogers), St. Thomas Hospital, and Departments of Medicine (Dr. Light) and Pediatrics (Dr Perkett), Vanderbilt University, Nashville, TN.

Correspondence to: Y. C. Gary Lee, MBChB, Department of Pulmonary Medicine, Saint Thomas Hospital, 4220 Harding Rd, Nashville, TN 37202; e-mail: ycgarylee{at}hotmail.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Recent studies have demonstrated high levels of vascular endothelial growth factor (VEGF) in exudative pleural effusions and a possible etiologic role. The factors regulating VEGF accumulation in the pleural space are unknown. Transforming growth factor (TGF)-ß is a potent stimulator of VEGF expression in vitro. We hypothesized that TGF-ß induces VEGF production in pleural tissues, and, hence, the pleural fluid VEGF levels should correlate with the levels of TGF-ß in pleural fluid of different etiologies.

Methods: Seventy pleural fluid samples were analyzed. These included 20 malignant, 13 post-coronary artery bypass grafting (CABG), 8 parapneumonic, 11 miscellaneous exudative, and 18 congestive heart failure (CHF) pleural effusions.

Results: Pleural fluid VEGF levels showed good correlation with those of TGF-ß1 (r = 0.58; p < 0.0001), TGF-ß2 (r = 0.43; p < 0.001), and lactate dehydrogenase (r = 0.65; p < 0.001). The levels of TGF-ß1 and TGF-ß2 also were correlated (r = 0.60; p < 0.0001). The median levels of TGF-ß1 (2,480 pg/mL) and TGF-ß2 (266 pg/mL) in the CHF group were significantly lower than those in the malignant (TGF-ß1, 4,902 pg/mL; TGF-ß2, 428 pg/mL), post-CABG (TGF-ß1, 5,456 pg/mL; TGF-ß2, 377 pg/mL), parapneumonic (TGF-ß1, 5,024 pg/mL; TGF-ß2, 464 pg/mL), and miscellaneous exudate groups (TGF-ß1, 7,690 pg/mL; TGF-ß2, 369 pg/mL). There was no significant difference in TGF-ß1 and TGF-ß2 levels among the four exudate groups.

Conclusions: VEGF levels in pleural effusions are significantly correlated with the levels of TGF-ß1 and ß2 isoforms. VEGF, TGF-ß1, and TGF-ß2 levels were all higher in exudative effusions than in effusions secondary to CHF.

Key Words: pleural effusions • transforming growth factor-ß • vascular endothelial growth factor


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Vascular endothelial growth factor (VEGF) is a key cytokine in the control of vascular permeability and is postulated to be important in pleural fluid formation.1 Recent studies have confirmed the presence of high levels of VEGF in exudative, especially malignant and inflammatory, effusions.1 2 In addition, VEGF receptors are present in the mesothelial cells1 of healthy and diseased human pleurae.

However, the factors regulating VEGF levels in pleural fluid are unknown. In vitro, transforming growth factor (TGF)-ß is one of the most potent stimulators for the production of VEGF in various cell lines,3 but, to our knowledge, the relationship between VEGF and TGF-ß in pleural diseases has not been studied. TGF-ß is a multifunctional cytokine that stimulates cell proliferation and angiogenesis in areas of inflammation.4 It can alter the morphology of mesothelial cells and increase their permeability.5 TGF-ß is produced by and acts on mesothelial cells6 and may serve as an important mediator in the pathogenesis of pleural diseases. High levels of TGF-ß have been demonstrated in pleural effusions from patients with malignant mesothelioma,7 tuberculous pleurisy,8 and sepsis.9

In mammals, TGF-ß consists of the following three isoforms: TGF-ß1, TGF-ß2, and TGF-ß3.10 Although these isoforms have similar actions in vitro, there have been reports of differences in their actions11 and distribution12 in vivo.

To our knowledge, there has been no comprehensive study comparing the levels of the TGF-ß isoforms in the common categories of pleural effusion. More importantly, the interrelationships among VEGF, TGF-ß1, and TGF-ß2 have not been investigated. We hypothesized the following: (1) that TGF-ß stimulates VEGF production in pleural tissues and, hence, that the pleural fluid VEGF levels would correlate with those of TGF-ß1 and TGF-ß2 isoforms; and (2) the levels of pleural fluid TGF-ß isoforms would be different in effusions of various etiologies.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Seventy pleural fluid samples were selected randomly from patients who underwent thoracentesis in our hospital between August 1, 1997, and June 30, 1998. Five of these patients had been included in our previous study of VEGF levels in pleural effusions.2 The clinical diagnoses of the pleural effusions were verified independently by at least one qualified pulmonologist (Y.C.G.L., R.M.R., or R.W.L.). This study was approved by the Institutional Review Board of Saint Thomas Hospital, and all patients signed an informed consent.

A pleural effusion was categorized as malignant if the results of pleural fluid cytology testing or pleural biopsy were positive for malignancy or if the patient had a known metastatic malignancy with no other explanation for the effusion. Of the 20 patients in the malignant effusion group, 14 had primary lung carcinomas (5 small cell, 5 adenocarcinoma, 2 squamous cell, 1 large cell, and 1 non-small cell carcinoma), 3 had breast carcinomas, 1 had colonic carcinoma, 1 had adenocarcinoma of unknown origin, and 1 had melanoma. A parapneumonic effusion was defined as one associated with bacterial pneumonia, including empyema (n = 3). A post-coronary artery bypass grafting (CABG) effusion was defined as one that developed within the first 3 months after coronary artery bypass surgery, with or without heart valve replacement with no other identifiable causes (eg, congestive heart failure [CHF], chylothorax, or infection). All other exudative effusions were included in the miscellaneous exudate group. The diagnoses of the effusions in the miscellaneous group are listed in Table 1 . A pleural effusion was attributed to CHF if it was a transudative effusion in a patient with symptoms and signs of CHF who responded to appropriate therapy. Exudates and transudates were classified according to the criteria of Light et al.13


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  		Table 1.. Causes of Pleural Effusion in the Miscellaneous Group (n = 11)

 
At the time of the thoracentesis, pleural fluid was collected in an ethylenediamine tetraacetic acid tube for the measurement of the total and differential WBC count, in a citrated tube for VEGF and TGF-ß quantification, and in a plain tube for glucose, protein, and lactate dehydrogenase (LDH) analysis. For cytokine quantification, the pleural fluid aspirates were immediately centrifuged at 3,000 rotations/min for 20 min at 4°C. The supernatant was stored at -70°C until analysis. RBC and WBC counts were obtained by manual microscopy. The differential WBC count was obtained by manually counting 100 cells on a smear stained with Wright’s stain after the cells had been concentrated by cytocentrifugation at 2,000 rotations/min for 10 min. Glucose, protein, and LDH concentrations were measured using an automated analyzer (Vitro Model 950; Johnson & Johnson; New York, NY).

VEGF, TGF-ß1, and TGF-ß2 concentrations were determined using an enzyme-linked immunosorbent assay kit (R&D Systems; Minneapolis, MN). All samples were acidified to convert all TGF-ß present to the immunoreactive form for measurement. There was no detectable cross-reactivity between the TGF-ß1 and TGF-ß2 isoforms using this commercial method.14 Measurements were made by the Microplate Manager 4.0 (Bio-Rad Laboratories; Hercules, CA) at a wavelength of 450 nm (reference wavelength, 540 nm). The coefficient of variance for the measurements of VEGF, TGF-ß1, and TGF-ß2 were 12%, 7%, and 16%, respectively.

Statistical Analysis
Since the pleural fluid VEGF, TGF-ß1, TGF-ß2, and LDH levels were not normally distributed, log transformation was performed on these data before analysis. One-way analysis of variance was used to compare their levels among subgroups and Tukey test was used to perform multiple comparison procedures. If the log-transformed data did not satisfy the normality and equal variance tests, Kruskal-Wallis one-way analysis of variance on ranks was used to compare the levels among subgroups and the Dunn test was used to perform multiple comparison procedures. Correlation was analyzed with the Pearson correlation test. In the stepwise multiple regression analysis, the percentage of total variance accounted for by the independent variables was reported in terms of the square of the multiple correlation coefficient (r2). A p value < 0.05 was considered significant. All data were analyzed with statistic computer software (SigmaStat, version 2.03; SPSS; San Rafael, CA).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The median levels of pleural fluid VEGF, TGF-ß1, and TGF-ß2 were all higher for the groups of patients with malignant, post-CABG, parapneumonic, and miscellaneous exudative effusions than the group with CHF (Fig 1 ). The median levels of pleural fluid protein and LDH in the different subgroups are presented in Table 2 . The difference in VEGF levels between the CHF group and the malignant and parapneumonic groups were statistically significant (p < 0.05). TGF-ß1 levels in the CHF patients were significantly (p < 0.05) lower when compared with any of the other four groups. There were no significant differences in the levels of VEGF, TGF-ß1, or TGF-ß2 among the four exudative subgroups.



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  		Figure 1.. Top: VEGF levels in pleural fluid according to diagnosis groups. Middle: TGF-ß1 levels in pleural fluid according to diagnosis groups. Bottom: TGF-ß2 levels in pleural fluid according to diagnosis groups. The pleural fluid VEGF, TGF-ß1, and TGF-ß2 levels were significantly lower in the CHF group when compared with the other four exudative effusion groups.

 

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  		Table 2.. The Protein and LDH Concentrations of Pleural Fluids in the Different Diagnostic Groups*

 
The VEGF level was significantly correlated with the levels of TGF-ß1 (r = 0.58; p < 0.0001; Fig 2 , top) and TGF-ß2 (r = 0.43; p < 0.001). The levels of TGF-ß1 and TGF-ß2 were correlated (r = 0.60; p < 0.0001) in the entire cohort (Fig 2 , bottom). When stepwise multiple regression analysis was performed, the addition of TGF-ß2 to TGF-ß1 alone did not significantly reduce the variance. Likewise, the correlation between the VEGF level and the sum of TGF-ß1 and TGF-ß2 levels was identical (r = 0.58; p < 0.0001) to that of TGF-ß1 alone.



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  		Figure 2.. Top: correlation of VEGF and TGF-ß1 levels in pleural fluids. Bottom: correlation of TGF-ß1 and TGF-ß2 levels in pleural fluids.

 
The correlations among VEGF, TGF-ß1, TGF-ß2 and LDH in the whole cohort and in different subgroups are presented in Table 3 . LDH is the only chemical parameter that correlated significantly with the concentrations of all three of the following cytokines studied: TGF-ß1 (r = 0.62; p < 0.0001); TGF-ß2 (r = 0.50; p < 0.0001); and VEGF (r = 0.65; p < 0.0001). TGF-ß1 levels were also statistically correlated with protein concentration (r = 0.47; p < 0.0001), RBC counts (r = 0.52; p < 0.0001), and total WBC counts (r = 0.28; p = 0.02). None of the other chemical or hematologic parameters tested were significantly correlated with VEGF, TGF-ß1, or TGF-ß2.


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  		Table 3.. r Values of TGFß Isoforms, VEGF, and LDH in the Whole Study Population and in the Different Diagnostic Groups

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Pleural effusion is a common clinical problem, but the mechanism of pleural effusion formation in pathologic states remains poorly understood. Cytokines are important mediators in pleural inflammation and fluid accumulation.15 To our knowledge, this is the first study to demonstrate that VEGF levels in pleural effusions are significantly related to the levels of TGF-ß1 and TGF-ß2. TGF-ß2 level also correlates significantly with that of TGF-ß1. The median levels of VEGF, TGF-ß1, and TGF-ß2 were higher in the malignant, post-CABG, parapneumonic, and miscellaneous exudate groups than in the CHF group. The pleural fluid levels of VEGF, TGF-ß1, and TGF-ß2 were all significantly correlated with the LDH concentration in the effusions.

VEGF is a selective endothelial mitogen and is 10,000 times more potent than histamine in enhancing vascular permeability.16 VEGF has been postulated to be an important mediator in the formation of pleural and peritoneal fluid.17 It is present at high levels in exudative pleural effusions and ascites.1 2 18 In a mouse model, tumor cells implanted in the peritoneal cavity secreted VEGF, which increased the permeability of microvessels lining the peritoneal cavity.19 The ascites volume increased in parallel with the concentration of VEGF.

Kraft et al17 showed that the VEGF levels in malignant pleural and peritoneal effusions were up to 10-fold higher than in the corresponding serum, indicating that local production rather than diffusion from serum is the main source of VEGF in effusions. Fms-like tyrosine kinase-1 receptors for VEGF are present in both healthy and inflamed human pleural tissues. This implies that intrapleural VEGF has an active biological role in the pleura.1 Little is known, however, about the mechanism that leads to the accumulation of VEGF in pleural effusions. In vitro, TGF-ß is one of the most potent stimulators of VEGF production in various animal and human cell lines.3 20 21 In human synovial fibroblasts, TGF-ß was the strongest inducer of VEGF secretion when compared with other cytokines.20 Given this in vitro evidence, we speculate that TGF-ß stimulates the release of VEGF from the mesothelial cells in vivo. The VEGF that is released in turn increases the capillary permeability in the pleura and leads to increased pleural fluid formation. Although our study cannot prove a causal relationship, the correlation between VEGF and TGF-ß levels in the pleural fluid supports this hypothesis.

TGF-ß is a multifunctional cytokine. It can alter the morphology of mesothelial cells in vitro and can increase the size of the intercellular spaces and, hence, the permeability of mesothelial cell monolayers.5 We recently demonstrated that intrapleural injection of TGF-ß2 in rabbits results in the production of a significant amount of pleural fluid in a dose-dependent fashion.22 In humans, TGF-ß is present in high levels in tuberculous pleural effusions8 and in effusions from mesotheliomas and metastatic lung carcinomas.7

The origin of pleural fluid TGF-ß is unknown. It could move passively from the blood or could be synthesized by the cells on the pleural surface or in the pleural fluid. The normal serum level of TGF-ß1 is in the order of 10 ng/mL.10 Without the corresponding serum TGF-ß isoform levels, we cannot fully exclude the possibility that at least some of the pleural fluid TGF-ß originated from passive diffusion from the blood. Mesothelial cells are capable of secreting TGF-ß,23 and they may account for the majority of TGF-ß in effusions. Once present, TGF-ß is capable of stimulating cells in the vicinity (in this case, the mesothelial cells and the inflammatory cells) to continue the local production of TGF-ß.4

Pleural inflammation from infection (in parapneumonic effusion) and trauma (in post-CABG effusion) are the likely initial stimuli for TGF-ß production. Most malignant cells produce TGF-ß24 25 and are the probable source of TGF-ß in malignant effusions. In patients with CHF, the pleura remains normal, which may explain the low levels of TGF-ß1. While monocytes, macrophages, and lymphocytes26 27 can produce TGF-ß and VEGF, our data showed a poor correlation between total (and differential) WBC counts and the levels of VEGF and TGF-ß. In a study of pleural and peritoneal effusions, Yeo et al18 found no correlation between the VEGF level in effusions and the total number of WBCs, neutrophils, and lymphocytes, or the percentage of any type of WBCs. We share the same observation in this study as well as in our previous publication.2 However, Yeo et al18 did report a correlation of VEGF level with monocyte concentration (r = 0.59). This correlation was not confirmed either in our previous study2 or in the present one (total samples, 135). The WBCs are, therefore, unlikely to be the main source of these cytokines in pleural effusions. It is likely that the TGF-ß in the pleural effusion originates from a combination of the above sources.

Our results showed that the pleural fluid LDH level, a marker of pleural inflammation, was strongly correlated to VEGF, TGF-ß1, and TGF-ß2 levels. This would be in keeping with the hypothesis that inflammation of the pleural tissue acts as a trigger for the accumulation of these cytokines in the pleural space.

In mammals, TGF-ß exists in the following three isoforms: TGF-ß1, TGF-ß2, and TGF-ß3. Although they have similar biological properties,4 10 differences in temporal and spatial distribution6 13 have been reported. Each isoform is regulated by a different promoter region,28 and TGF-ß1 and TGF-ß2 knockout mice have shown no phenotype overlap indicating numerous noncompensated functions between the two isoforms.29 TGF-ß1 exhibited stronger affinity for TGF-ß receptors on the rat lung fibroblast than did TGF-ß2. However, in the lung vasculature, TGF-ß2, but not TGF-ß1, was highly expressed in the smooth muscle cells.11 12 These observations emphasize the importance of examining the different isoforms of TGF-ß. Our result revealed that both the TGF-ß1 and TGF-ß2 isoforms were detectable and correlated. However, the correlation of these two isoforms varied between subgroups and may imply different actions of these isoforms in various pleural diseases. A larger study will be required to confirm and further elucidate this observation.

In conclusion, the present study demonstrated a significant correlation between the pleural fluid levels of VEGF and both TGF-ß1 and TGF-ß2. Also, the pleural fluid levels of TGF-ß1 are higher in common types of exudative effusions than in CHF effusions. TGF-ß, alone or with VEGF, is probably an important factor in the formation of exudative pleural fluid. These observations may be important, as antibodies to TGF-ß and VEGF are now available and may provide a new approach to the future management of pleural effusions.


   Footnotes
 
Abbreviations: CABG = coronary artery bypass grafting; CHF = congestive heart failure; LDH = lactate dehydrogenase; TGF = transforming growth factor; VEGF = vascular endothelial growth factor

Supported by the Saint Thomas Foundation, and the United States-New Zealand Fulbright Graduate Award (Y.C.G.L.).

Received for publication December 9, 1999. Accepted for publication March 16, 2000.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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