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(Chest. 2004;126:1522-1528.)
© 2004 American College of Chest Physicians

Talc Pleurodesis*

Basic Fibroblast Growth Factor Mediates Pleural Fibrosis

Veena B. Antony, MD, FCCP; Najmunnisa Nasreen, PhD; Kamal A. Mohammed, PhD; Peruvenba S. Sriram, MD; Wolfgang Frank, MD; Nicolas Schoenfeld, MD and Robert Loddenkemper, MD, FCCP

* From the Division of Pulmonary and Critical Care Medicine (Drs. Antony, Nasreen, and Mohammed), College of Medicine, University of Florida, Gainesville, FL; and Lungenklinik Heckeshorn (Drs. Frank, Schoenfeld, and Loddenkemper), Berlin, Germany.

Correspondence to: Veena B. Antony, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Florida, PO Box 100225, Gainesville, FL 32610-0225; e-mail: antonvb{at}medicine.ufl.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Patients with recurrent pleural effusions secondary to malignancy are subjected to pleurodesis if clinically indicated. Pleurodesis involves the introduction of a sclerosing agent into the pleural space. Talc is one of the most commonly used sclerosing agents in treating patients with recurrent, symptomatic malignant pleural effusions. However, the mechanisms whereby talc mediates pleural fibrosis remain unclear. We hypothesized that the intrapleural instillation of talc induces the pleural mesothelial production of basic fibroblast growth factor (bFGF), which is responsible for pleural fibrosis.

Methods: Samples of pleural fluid collected from 23 patients with malignant pleural effusions and 6 patients with congestive heart failure (control group) were included in this study. A tumor grading scale (1 to 9) was used to demonstrate the extent of the tumor. In vitro pleural mesothelial cells (PMCs) were activated with talc, and the conditioned medium was collected to evaluate bFGF levels by enzyme-linked immunosorbent assay. The bFGF-induced proliferation of fibroblasts was studied by [3H]thymidine incorporation. The messenger RNA expression of bFGF in talc-activated PMCs was determined by Northern analysis.

Results: In this study, we demonstrated that patients who have undergone successful pleurodesis following intrapleural talc insufflation have significantly higher levels of bFGF in their pleural fluid compared to those who do not respond to pleurodesis. In addition, we found a significant negative correlation between bFGF levels and tumor size. Talc-activated PMCs produce significantly higher levels of bFGF compared to control, which correlates with bFGF messenger RNA expression in PMCs stimulated with talc. The neutralization of pleural fluids and conditioned medium from talc-stimulated PMCs with bFGF antibodies significantly inhibits the bFGF-induced proliferation of pleural fibroblasts.

Conclusions: An important outcome of this study was the finding that patients with extensive tumor involvement of the pleural mesothelium have a significantly lower pleural fluid bFGF response to talc compared to those who have limited involvement. Patients with limited pleural disease and higher bFGF responses go on to have successful pleurodesis, demonstrating that the presence of a mesothelium that is free of tumor enhances the possibility of success. In vitro PMCs stimulated with talc release biologically active bFGF.

Key Words: basic fibroblast growth factor • mesothelial cells • pleurodesis • talc • thoracoscopy


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The pleura is a metabolically active monolayer of cells that envelops the lungs. These specialized cells are known to play an active role in the regulation of inflammation in the pleural space.1 Under normal circumstances, the parietal and visceral pleura are intimately opposed, with a small quantity of pleural fluid. This homeostatic balance is drastically altered following metastatic seeding of the pleural surface with malignant cells or the development of a mesothelioma. In clinically symptomatic patients, talc pleurodesis is one therapeutic strategy used for palliation.

Talc (3 MgO, 4SiO2, and H2O) is considered to be one of the most successful sclerosing agents for pleurodesis, whether it is insufflated into the pleural space via thoracoscopy or is administered in the form of talc slurry, when compared to doxycycline, tetracycline, and bleomycin234 Talc instillation in the form of a slurry through a chest tube or insufflation following thoracoscopy has been shown to be equally efficacious.5 Talc has been shown to have a > 90% success rate as a sclerosing agent.6 During pleurodesis, the visceral pleura adheres to and is indistinguishable from the parietal pleura because of the development of dense fibrosis. The mechanism whereby talc induces this exuberant fibrotic response that results in the obliteration of the pleural space remains unclear.

Basic fibroblast growth factor (bFGF), or fibroblast growth factor-2, is one of the fibroblast growth factor families, which comprise a group of structurally related polypeptides consisting of 18 members.7 bFGF is mitogenic for a variety of cells including fibroblasts, smooth muscles, and endothelial cells, and is also a known angiogenic factor.78910 In this study, we demonstrate that patients with malignant pleural effusions who had undergone successful pleurodesis following intrapleural talc insufflation had significantly higher levels of bFGF in their pleural fluid compared to those who did not respond to pleurodesis. Importantly, in vitro supernatants of talc-stimulated mesothelial cells were found to contain significant quantities of bFGF and fibroblast growth-stimulating activity. In addition, we were able to demonstrate a correlation between the extent of pleural involvement by tumor, and pleural fluid bFGF levels and outcomes of pleurodesis.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Study
A total of 23 patients with malignant pleural effusions were prospectively studied and subjected to thoracoscopy followed by talc pleurodesis. Eleven patients had lung cancer, 6 patients had breast cancer, 5 patients had mesothelioma, and 1 patient had metastatic melanoma. All patients in the study gave informed consent, and the study was performed in accordance with institutional review board guidelines. Patients in whom malignant pleural effusions were diagnosed by pleural fluid cytology and who fulfilled the American Thoracic Society/European Respiratory Society guidelines for the management of pleural effusions were included in the study. Exclusion criteria followed American Thoracic Society/European Respiratory Society guidelines and included the following: (1) terminal disease, (2) trapped lung, and (3) blocking diathesis. Six patients who presented with intractable right-sided pleural effusions despite receiving maximal therapy underwent thoracoscopy without talc pleurodesis and were included as the control group. Of these patients, four had effusions secondary to congestive heart failure, while two had nephrotic syndrome. Their pleural spaces were evaluated for possible comorbid conditions or pathology. The mean (± SD) age group of the patients included in this study was 64.2 ± 12.6 years (range, 42 to 88 years), of whom 11 were men and 12 were women, while the control group had 4 men and 2 women.

Medical thoracoscopy was performed under local anesthesia and conscious sedation in all patients, and pleural lesions were graded as previously described.1112 In brief, the appearance, location, and extent of the lesions were noted. The tumors were classified as "diffuse," when they were disseminated over the pleural layer, or "massive," when no normal pleural zones were observed among the scattered lesions. This classification established which pleural surface was most affected, depending on the extent of pleural surface involvement. The visceral, parietal, and diaphragmatic pleural surfaces were studied and incorporated in the tumor-rating score.

The pleural lesions observed by thoracoscopy were classified on a scale of 1 to 9 by the same physician (N.S.). One point was assigned to lesions isolated on the pleural layer, 2 points to diffuse lesions, and 3 points to massive lesions. The tumor rating obtained from the parietal, visceral, and diaphragmatic areas then were added together in order to determine the group in which each patient was to be placed.13 Talc pleurodesis was performed after diagnosis in all the patients with malignant pleural effusions.

During thoracoscopy following fluid removal from the pleural cavity, 2 to 4 g of sterile, asbestos-free, lipopolysaccharide-free talc was instilled by insufflation (poudrage) into the pleural cavity under visual control, which ensured homogeneous distribution. On completion of the procedure, a chest tube was left in place in all patients. The total amount of pleural fluid drainage from the chest tube in patients who responded to the procedure was < 200 mL following talc insufflation. The outcome of pleurodesis was evaluated 30 days after the procedure and at 3-month intervals until death. Pleurodesis was termed successful when the pleural effusion did not recur at any time during the follow-up until the death of the patient, while it was termed a failure if the pleural effusion recurred at any time during the follow-up period.

Pleural Fluid Collection
Pleural fluid was obtained via thoracentesis from patients according to a protocol approved by the institutional review board. Pleural fluid also was obtained at the beginning of thoracoscopy (baseline), immediately after thoracoscopy, and at 2, 4, 12, and 24 h postthoracoscopy. All samples were centrifuged, and the supernatants were aliquoted into 2-mL samples and frozen at –70°C until further tests were performed.

Talc Preparation
Talc (3 MgO, 4SiO2, and H2O) particles were suspended in endotoxin-free H2O at a concentration of 4,000 µg/mL, as described previously.14 The particles were washed and then sterilized in an autoclave. The concentrated stock samples of talc had undetectable levels of endotoxin, as determined with an amoebocyte lysate assay (Limulus; Sigma; St. Louis, MO).

Pleural Mesothelial Cell Culture
Human pleural mesothelial cells (PMCs) in primary culture (ATCC; Manassas, VA) were used with between four and eight passages. The cells were resuspended in culture media (Media-199; Gibco Laboratories; Grand Island, NY) containing 10% fetal bovine serum (Atlanta Biologicals; Norcross, GA), penicillin (100 U/mL), and streptomycin (100 µg/mL). The cells were plated in 75-cm2 culture flasks (Corning Costar Corporation; Acton, MA) and were incubated at 37°C in 5% CO2 and 95% air. When the cells were confluent, they were trypsinized and seeded into culture flasks/transwell chambers, as required for different assays. The PMCs were stimulated with talc (4 µg/cm2) or were left untreated in serum-free medium for 24 h, as reported earlier.14 The PMC viability was tested at the end of 24 h by trypan blue dye exclusion. The concentration selected did not cause lactate dehydrogenase release from PMCs.

bFGF Analysis by Enzyme-Linked Immunosorbent Assay
bFGF concentrations in pleural fluids and in talc-stimulated PMC supernatants were measured by a "sandwich" enzyme-linked immunosorbent assay kit (R&D systems Inc; Minneapolis, MN), as previously described.15

Effect of bFGF on Cell Proliferation
Human fetal lung fibroblasts were seeded into 24-well plates (1 to 5 x 105 cells per well) in the presence of Dulbecco modified Eagle medium containing 5% fetal calf serum. Cells were washed three times and then cultured for an additional 24 h in Dulbecco modified Eagle medium containing 0.1% fetal calf serum. Cultures then were supplemented with pleural fluids. After 20 h at 37°C, [3H]thymidine (1.8 µCi per well; 90 µCi/mL) was added, and after 4 h the incorporation of radiolabeled thymidine was determined, as described previously.16

Northern Blot Analysis
Total cellular RNA from PMCs was isolated, as described earlier.17 The RNA was separated by electrophoresis in 1% agarose gel with formaldehyde, transblotted to nitrocellulose, baked, prehybridized, and hybridized with a bFGF-specific oligo probe. Blots were washed, and autoradiographs were prepared.18

Statistical Analysis
Data were analyzed by using a statistical software package (SigmaStat; Apple Computer; Cupertino, CA). The results are expressed as the mean ± SE. The data were analyzed by analysis of variance with the use of the Student-Newman-Keuls test for multiple comparisons, and the results were considered to be significant if the p value was < 0.05.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Outcome of Pleurodesis
Twenty-three patients underwent thoracoscopy followed by talc pleurodesis; 16 were successful (70%). The results are depicted in Table 1 along with the etiology of the malignant pleural effusions. As mentioned above, six patients with benign pleural effusions underwent thoracoscopy without talc poudrage as a control group.


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  		Table 1.. Tumor Origin and Outcome of Talc Pleurodesis in Patients With Malignant Effusions

 
Talc Induces bFGF Production in the Pleural Space
Serial measurements of bFGF by enzyme-linked immunosorbent assay were performed on the pleural fluid samples of the patients following thoracoscopy. Patients were categorized as having successful pleurodesis or failed pleurodesis, or as being control subjects (ie, those patients who underwent thoracoscopy without talc instillation). While bFGF levels remained unchanged in the control patients, in patients who went on to have a successful pleurodesis, a significant increase in bFGF levels was noticed (Fig 1 ). A 10-fold increase in bFGF levels was noted at 2 h postpleurodesis in patients who had a successful pleurodesis compared to control subjects. The bFGF levels measured after 4 h steadily tapered off for > 24 h but remained higher than the baseline level. On the other hand, bFGF levels in patients who experienced pleurodesis failure were significantly lower until 12 h compared to patients in the successful pleurodesis group. However, when compared to control subjects, the bFGF levels in patients in the pleurodesis failure group were significantly higher after 4 h.



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  		Figure 1.. bFGF levels in the pleural fluid of successful and failed pleurodesis patients. Values are given as the mean ± SE of three separate experiments. Statistical significance (* = p < 0.001) was obtained as a comparison with the control group.

 
Talc Induces bFGF Production in Human PMCs In Vitro
Human PMCs were stimulated with asbestos-free, lipopolysaccharide-free talc, or were left untreated for 4 h, and supernatants were collected. Unstimulated PMCs released negligible amounts of bFGF. On the other hand, in talc-treated mesothelial cell cultures, a fivefold increase in bFGF levels was noted compared to those in control subjects (Fig 2 ). The increase in bFGF levels in talc-treated PMC cultures correlated temporally with the aforementioned in vivo findings in patients who had successfully undergone pleurodesis.



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  		Figure 2.. bFGF release in PMCs stimulated with talc. PMCs were stimulated with talc for 4 h, at which time bFGF levels were measured. Values are given as the mean ± SE of three separate experiments. Statistical significance (* = p < 0.001) was obtained as a comparison with the control group.

 
Talc Mediates bFGF Messenger RNA Expression in Human PMCs
Human PMCs were treated with talc or were left untreated for 4 h, and bFGF messenger RNA expression was determined by Northern blot analysis. The autoradiograph demonstrates that talc induces bFGF messenger RNA expression in PMCs (Fig 3 ). Resting PMCs did not express bFGF messenger RNA.



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  		Figure 3.. bFGF messenger RNA expression in PMCs. Lane 1, PMCs incubated in serum-free medium; lane 2, PMCs stimulated with talc at 4 h, as described in the "Materials and Methods" section. Top, A: Northern blot analysis of bFGF messenger RNA by PMCs. Bottom, B: Ribosomal RNA 28S and 18S stained with ethidium bromide, indicating equal loading of total RNA. This is representative of three independent experiments.

 
Talc Induces Fibroblast Growth Bioactivity in Pleural Fluids
Human fetal lung fibroblasts were cultured in pleural fluids, and [3H]thymidine uptake was assessed. The test was performed using supernatants of individual patient pleural fluid samples instead of using a pooling of all samples. The proliferation of human fetal lung fibroblasts was considerably enhanced in the presence of pleural fluid samples obtained from patients who had undergone a successful pleurodesis (Fig 4 ). In comparison, pleural fluid from patients who failed pleurodesis did not cause a marked proliferation. The addition of anti-bFGF antibody to fluids from patients with a successful pleurodesis caused a 50 to 60% reduction in fibroblast growth, indicating a bFGF-specific response. The isotype antibody did not show any effect on fibroblast growth.



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  		Figure 4.. Fibroblast proliferation by [3H]thymidine incorporation. Pleural fluid obtained after 4 h from patients who had a successful talc pleurodesis (16 patients) or failed talc pleurodesis (7 patients) were tested as described in the "Materials and Methods" section. Values are given as the mean ± SE of three separate experiments that were run in triplicate. Statistical significance (* = p < 0.001; $ = p < 0.05) was obtained from a comparison with no-antibody samples. PF = pleural fluid; Ab = antibody.

 
Talc Induces Fibroblast Growth Activity in Supernatants of Stimulated Pleural Mesothelial Cells
Human PMCs were exposed to talc or were left untreated as control subjects in serum-free media for > 4 h, and the supernatants were obtained. Human fetal lung fibroblasts then were cultured in the supernatants, and [3H]thymidine uptake was assessed (Fig 5 ). Talc-stimulated PMC supernatants induced a twofold increase in fibroblast proliferation when compared to resting PMCs. The addition of anti-bFGF antibody caused a significant reduction (ie, 30 to 40%) in fibroblast growth, indicating a bFGF-specific response. The isotype antibody did not show any effect on fibroblast growth.



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  		Figure 5.. The effect of talc-stimulated PMC supernatants on fibroblast proliferation in vitro. Fibroblast proliferation by [3H]thymidine uptake was measured as described in the "Materials and Methods" section. The results are given as the mean ± SE of three separate experiments. Statistical significance (* = p < 0.001) was obtained in comparison with cultures. CM = conditioned medium.

 
Correlation Between Tumor Extent and bFGF Levels in Patients With Successful and Unsuccessful Pleurodesis
Tumor size and the extent of the involvement of the pleural surface were evaluated at the time of thoracoscopy, and were compared with the results of pleurodesis and pleural fluid bFGF levels. Sixteen patients underwent successful pleurodesis and were noted to have significantly elevated bFGF levels compared to the seven patients who experienced pleurodesis failure. Among the patients who underwent successful pleurodesis, 60% had a tumor rating score ranging from 1 to 3, while only two patients had a score of 5 to 6 with massive involvement of the visceral and parietal pleura. On the other hand, all seven patients who failed pleurodesis and had low pleural fluid bFGF levels had massive tumor involvement of the pleural surfaces, with tumor scores ranging from 6 to 9. In a simple linear regression model (Fig 6 ), bFGF levels were used as the response variable, and the tumor score as the predictor variable. bFGF levels were found to have a significant impact on tumor score (p < 0.001; r = 0.900). There was a significant negative correlation between the bFGF levels and tumor size in all the samples included in this study. The equation can be described as bFGF = 564.00 – (63.7 x tumor score).



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  		Figure 6.. The correlation of tumor score and pleural fluid bFGF levels in patients who underwent successful and failed pleurodesis. There was a significant (p < 0.05) negative correlation between the bFGF levels (as the response variable) and tumor score (as the predictor variable) [r = 0.900].

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The annual incidence of malignant pleural effusions in the United States is approximately 150,000.4 A significant proportion of these patients eventually become symptomatic with recurrent accumulations of pleural fluid. Patients with recurrent symptomatic malignant pleural effusions are often subjected to chemical pleurodesis. In the present study, we have demonstrated that bFGF may play an important role in the development of pleurodesis in patients who receive talc insufflation via thoracoscopy. Patients who underwent a successful pleurodesis had significantly higher levels of bFGF when compared to those who either failed pleurodesis or had thoracoscopy but did not have talc insufflated into the pleural space. Importantly, the addition of the bFGF antibody to the pleural fluids obtained from these patients caused a significant decrease in fibroblast growth activity. Another important finding was the negative correlation noted with tumor size and bFGF levels. Patients with extensive tumor involvement in the pleural surface had significantly lower bFGF levels in the pleural fluid samples obtained than did patients with limited involvement of the pleural surface who demonstrated markedly higher bFGF levels and went on to have a successful pleurodesis.

In vitro, PMCs stimulated with talc released higher levels of biologically active bFGF when compared to controls. This correlated with bFGF messenger RNA expression in PMCs stimulated with talc. Our findings are interesting because the mechanism of pleurodesis has not been defined. It is assumed that a fibrin network between the visceral and parietal pleura forms rapidly, and that fibroblasts migrate and proliferate on the fibrinous adhesions between the two surfaces. This exuberant proliferation of fibroblasts is associated with the loss of the margins demarcating the visceral and parietal pleura as separate entities.

Previous investigations from our laboratory have demonstrated that an acute inflammatory reaction is initiated in the pleural space following the administration of talc, with an influx of neutrophils and mononuclear cells associated with an increase in interleukin-8 and monocyte chemoattractant protein-1 in pleural fluids.1419 This inflammatory response, however, does not explain the rapid development of fibrosis that is seen in patients who undergo pleurodesis procedures. Other investigators have demonstrated13 that the failure of talc pleurodesis was associated with an increased presence of fibrinolytic activity, as measured by the presence of d-dimer.

Peritoneal mesothelial cells secrete significant amounts of glycosaminoglycans, which may explain the release of bFGF by mesothelial cells.20 Proteoglycans have been known to sequester bFGF; however, PMC-derived bFGF may be released through the activation and degradation of extracellular matrix components by the influx of inflammatory cells into the pleural space during talc insufflation. Although both malignant and normal PMCs synthesize bFGF, our data demonstrate that normal PMCs contribute a significant portion of the bFGF seen in pleural fluids following talc insufflation. The significant negative correlation between tumor involvement of the pleura and bFGF levels demonstrates that the presence of a normal mesothelium was important to the rapid release of bFGF into the pleural space following talc insufflation. This also concurs with clinical information that suggests that patients with extensive involvement of the pleural space by a malignant tumor may have a poor response to a sclerotic procedure.1321 The results of the present study lend further credence to the argument for the early treatment of malignant pleural effusions when the pleura is not diffusely covered with malignant deposits.

Previous investigations have demonstrated an increased number of blood vessels and angiogenic activity on pleural surfaces in animals that have undergone talc pleurodesis.10 bFGF has been described to be an angiogenic factor and may contribute to the angiogenic activity in the pleural space.10 Importantly, bFGF has been demonstrated to induce vascular endothelial growth factor, which is a known angiogenic factor.22 It has been reported23 that the sclerosed pleura has significant fibrosis and collagen deposition but no angiogenic blood vessel formation. Studies also have shown that while bFGF has been noted to promote the secretion of transforming growth factor-ß, bFGF messenger RNA expression is induced by transforming growth factor-ß, indicating the presence of a positive feedback mechanism that accentuates fibrosis.2425

Our findings suggest that the talc-induced production of bFGF by PMCs may play a critical role in the development of pleural fibrosis in patients with symptomatic malignant pleural effusions. The process of fibrosis following pleurodesis is multifactorial, with one of the key players being bFGF. However, in order to better understand the mechanism of talc-induced pleural fibrosis, the involvement of other factors needs to be further investigated.


   Footnotes
 
Abbreviations: bFGF = basic fibroblast growth factor; PMC = pleural mesothelial cell

This work was supported by National Institutes of Health grant RO1 AI 45338–02.

Received for publication January 14, 2004. Accepted for publication June 18, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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