We investigate the mechanism of talc pleurodesis (TP) in 20 patients with recurrent malignant pleural effusion and 10 patients with nonmalignant pleural effusions. We measured IL-8 levels before and 6？h after TP and find a significant threefold increase (2.26？ng/mL ± 0.7 to 6.5？ng/mL 0.1), which explains the recruitment of inflammatory cells in these patients. We hypothesize that TP is enable by stimulating the mesothelial cells (MS) to secrete FGF. A significant tenfold increase in FGF-b (0.05？ng/mL ± 0.02 to 0.44？ng/mL 0.6) was seen 24？h after talc instillation ( ). In order to examine whether FGF-b is secreted by MS cells, MS recovered from CHF patients with recurrent pleural effusions were cultured for 48？h in the presence or absence of increasing concentrations of talc (from 100？ng/mL to 1？mg/mL). They produced significant levels of FGF-b in a dose dependent manner ( ). We hypothesized that a successful pleurodesis involves an early enhanced recruitment of inflammatory cells through a rise of IL-8 followed by enrollment of fibroblasts from the submesothelial space through increased mesothelial FGF-b production. 1. Introduction Recurrent pleural effusion in cancer patients is a common problem that significantly affects their quality of lives. Several palliative treatment options are available for malignant recurrent pleural effusion in cancer patients who are not responding to chemotherapy, repeated thoracocentesis, or chemical pleurodesis. The most widely used pleurodesis technique is based on the instillation of sclerosing agents into the pleural space. The therapeutic goal in the management of symptomatic patients with malignant pleural effusions is to achieve effective pleural sclerosis. The aim of the sclerosant agent is to irritate both pleurae and to induce mesothelial cell sloughing and subsequent formation of adhesions between the parietal and visceral surfaces. Although the agent must have irritant attributes, it needs to limit and even obviate adverse effects to the patient. Several sclerosing agents are used in clinical practice, among them doxycycline, minocycline, tetracycline, bleomycin, cisplatin, etoposide, fluorouracil, interferon-β, and corynebacterium parvum. Talc has minimal long-term adverse side effects and it was shown to be the most effective agent for preventing recurrences [1]. The mechanisms of pleurodesis have not yet been entirely understood. Diffuse pleural inflammation and fibrin deposition have been considered influential in the success of pleural symphysis [2]. In animal studies, histologic analysis of talc-treated
References
[1]
L. Kennedy, V. W. Rusch, C. Strange, R. J. Ginsberg, and S. A. Sahn, “Pleurodesis using talc slurry,” Chest, vol. 106, no. 2, pp. 342–346, 1994.
[2]
L. Kennedy, R. A. Harley, S. A. Sahn, and C. Strange, “Talc slurry pleurodesis. Pleural fluid and histologic analysis,” Chest, vol. 107, no. 6, pp. 1707–1712, 1995.
[3]
F. Rodriguez-Panadero, A. Segado, J. M. Juan, R. Ayerbe, I. T. Garcia, and J. Castillo, “Failure of talc pleurodesis is associated with increased pleural fibrinolysis,” American Journal of Respiratory and Critical Care Medicine, vol. 151, no. 3, part 1, pp. 785–790, 1995.
[4]
R. B. Goodman, R. G. Wood, T. R. Martin, O. Hanson-Painton, and G. T. Kinasewitz, “Cytokine-stimulated human mesothelial cells produce chemotactic activity for neutrophils including NAR-1/IL-8,” Journal of Immunology, vol. 148, no. 2, pp. 457–465, 1992.
[5]
C. C. Lin, C. C. Liu, and C. Y. Lin, “Changes in cell population and tumor necrosis factor, interleukin-6, and interleukin-8 in malignant pleural effusions after treatment with intrapleural tetracycline,” American Review of Respiratory Disease, vol. 147, no. 6, part 1, pp. 1503–1506, 1993.
[6]
V. B. Antony, K. J. Rothfuss, S. W. Godbey, J. A. Sparks, and J. W. Hott, “Mechanism of tetracycline-hydrochloride-induced pleurodesis: tetracycline-hydrochloride-induced pleurodesis,” American Review of Respiratory Disease, vol. 146, no. 4, pp. 1009–1013, 1992.
[7]
V. Agrenius, J. Chmielewska, O. Widstr？m, and M. Blomb？ck, “Pleural fibrinolytic activity is decreased in inflammation as demonstrated in quinacrine pleurodesis treatment of malignant pleural effusion,” American Review of Respiratory Disease, vol. 140, no. 5, pp. 1381–1385, 1989.
[8]
D. E. Griffith, A. R. Johnson, A. Kumar, D. B. Holiday, and S. Idell, “Growth factors for human pleural mesothelial cells in soluble products from formed clots,” Thrombosis Research, vol. 74, no. 3, pp. 207–218, 1994.
[9]
A. N. Hurewitz, K. Lidonicci, C. L. Wu, D. Reim, and S. Zucker, “Histologic changes of doxycycline pleurodesis in rabbits. Effect of concentration and pH,” Chest, vol. 106, no. 4, pp. 1241–1245, 1994.
[10]
A. Mathlouthi, A. Chabchoub, N. Labbene, et al., “An experimental anatomopathological study of pleural talcosis,” Revue des Maladies Respiratoires, vol. 9, no. 6, pp. 617–621, 1992.
[11]
M. Kuwahara, K. E. Bijwaard, D. M. Gersten, C. A. Diglio, and E. Kagan, “Mesothelial cells produce a chemoattractant for lung fibroblasts: role of fibronectin,” American Journal of Respiratory Cell and Molecular Biology, vol. 5, no. 3, pp. 256–264, 1991.
[12]
D. E. Griffith, A. R. Johnson, A. Kumar, D. B. Holiday, and S. Idell, “Growth factors for human pleural mesothelial cells in soluble products from formed clots,” Thrombosis Research, vol. 74, no. 3, pp. 207–218, 1994.
[13]
A. N. Hurewitz, K. Lidonicci, C. L. Wu, D. Reim, and S. Zucker, “Histologic changes of doxycycline pleurodesis in rabbits. Effect of concentration and pH,” Chest, vol. 106, no. 4, pp. 1241–1245, 1994.
[14]
M. Kuwahara, K. Verma, T. Ando, D. R. Hemenway, and E. Kagan, “Asbestos exposure stimulates pleural mesothelial cells to secrete the fibroblast chemoattractant, fibronectin,” American Journal of Respiratory Cell and Molecular Biology, vol. 10, no. 2, pp. 167–176, 1994.
[15]
V. B. Antony, K. J. Rothfuss, S. W. Godbey, J. A. Sparks, and J. W. Hott, “Mechanism of tetracycline-hydrochloride-induced pleurodesis. Tetracycline- hydrochloride-stimulated mesothelial cells produce a growth-factor-like activity for fibroblasts,” American Review of Respiratory Disease, vol. 146, no. 4, pp. 1009–1013, 1992.
[16]
R. C. Milanez, F. S. Vargas, L. B. Filomeno et al., “Intrapleural talc for the treatment of malignant pleural effusions secondary to breast cancer,” Cancer, vol. 75, no. 11, pp. 2688–2692, 1995.
[17]
V. B. Antony, J. W. Hott, S. L. Kunkel, S. W. Godbey, M. D. Burdick, and R. M. Strieter, “Pleural mesothelial cell expression of C-C (monocyte chemotactic peptide) and C-X-C (interleukin 8) chemokines,” American Journal of Respiratory Cell and Molecular Biology, vol. 12, no. 6, pp. 581–588, 1995.
[18]
E. Marchi, F. S. Vargas, M. M. P. Acencio et al., “Talc and silver nitrate induce systemic inflammatory effects during the acute phase of experimental pleurodesis in rabbits,” Chest, vol. 125, no. 6, pp. 2268–2277, 2004.
[19]
E. Marchi, F. S. Vargas, M. M. Acencio, L. Antonangelo, E. H. Genofre, and L. R. Teixeira, “Evidence that mesothelial cells regulate the acute inflammatory response in talc pleurodesis,” European Respiratory Journal, vol. 28, no. 5, pp. 929–932, 2006.
[20]
V. B. Antony, N. Nasreen, K. A. Mohammed et al., “Talc pleurodesis: basic fibroblast growth factor mediates pleural fibrosis,” Chest, vol. 126, no. 5, pp. 1522–1528, 2004.
[21]
E. H. Genofre, F. S. Vargas, L. Antonangelo et al., “Ultrastructural acute features of active remodeling after chemical pleurodesis induced by silver nitrate or talc,” Lung, vol. 183, no. 3, pp. 197–207, 2005.
[22]
N. Nasreen, D. L. Hartman, K. A. Mohammed, and V. B. Antony, “Talc-induced expression of C-C and C-X-C chemokines and intercellular adhesion molecule-1 in mesothelial cells,” American Journal of Respiratory and Critical Care Medicine, vol. 158, no. 3, pp. 971–978, 1998.
[23]
M. M. Acencio, F. S. Vargas, E. Marchi et al., “Pleural mesothelial cells mediate inflammatory and profibrotic responses in talc-induced pleurodesis,” Lung, vol. 185, no. 6, pp. 343–348, 2007.
[24]
N. Nasreen, K. A. Mohammed, S. Brown et al., “Talc mediates angiostasis in malignant pleural effusions via endostatin induction,” European Respiratory Journal, vol. 29, no. 4, pp. 761–769, 2007.
[25]
P. Lee, L. Sun, C. K. Lim, S. E. Aw, and H. G. Colt, “Selective apoptosis of lung cancer cells with talc,” European Respiratory Journal, vol. 35, no. 2, pp. 450–452, 2010.
[26]
S. C. Ribeiro, F. S. Vargas, L. Antonangelo et al., “Monoclonal anti-vascular endothelial growth factor antibody reduces fluid volume in an experimental model of inflammatory pleural effusion,” Respirology, vol. 14, no. 8, pp. 1188–1193, 2009.
[27]
L. R. Teixeira, F. S. Vargas, M. M. Acencio et al., “Blockage of vascular endothelial growth factor (VEGF) reduces experimental pleurodesis,” Lung Cancer, vol. 74, no. 3, pp. 392–395, 2011.
[28]
N. Decologne, M. Kolb, P. J. Margetts et al., “TGF-β induces progressive pleural scarring and subpleural fibrosis,” Journal of Immunology, vol. 179, no. 9, pp. 6043–6051, 2007.
