A Single Intrapleural Injection of Transforming Growth Factor- β₂ Produces an Excellent Pleurodesis in Rabbits

Abstract

The purpose of the present study was to determine whether the intrapleural injection of transforming growth factor beta(2) (TGF-beta(2)) would produce a pleurodesis in rabbits. Single intrapleural injections of TGF-beta(2) at doses of 5.00 microg (n = 12), 1.67 microg (n = 10), 0.50 microg (n = 10), or 0.167 microg (n = 4), or of the parenteral buffer alone (n = 5) were given in a volume of 2 ml to New Zealand white rabbits. Chest tubes were left in place for at least 72 h. Pleural fluid was aspirated at 24-h intervals and was measured and subjected to chemical analysis. The animals were killed 14 d after the injection. The intrapleural injection of TGF-beta(2) resulted in a dose-dependent pleurodesis (on a scale of 0 to 4, where 0 = no pleurodesis and 4 = complete pleurodesis) with mean scores of 3.6, 2.6, 1.5, 0.7, and 0.3 for the groups that received 5.0, 1.67, 0.50, and 0.167 microg of TGF-beta(2) and buffer alone, respectively. Intrapleural injection of the larger doses of TGF-beta(2) resulted in the formation of a large amount of pleural fluid. The fluid had a significantly lower white blood cell (WBC) count and lactate dehydrogenase (LDH) level than did the fluid that results from the intrapleural injection of 10 mg/kg doxycycline or 400 mg/kg talc slurry. On the basis of this study we conclude that a single intrapleural injection of TGF-beta(2) induces pleurodesis in a dose-dependent manner. A dose of 5.0 microg produced satisfactory pleurodesis in almost all of the rabbits so treated. Larger doses of TGF-beta(2) induced larger pleural effusions with relatively low pleural fluid WBC counts and LDH levels. The ability of TGF-beta to produce a pleurodesis in patients with recurrent pleural effusions or pneumothorax should be investigated. A single intrapleural injection of TGF-beta(2) may produce a pleurodesis both safely and painlessly.

Evidence that mesothelial cells regulate the acute inflammatory response in talc pleurodesis

“…Talc may injure the mesothelial layer or may stimulate monocytes or mesothelial cells to produce a local reaction mediated by major inflammatory cytokines [10,11]. Among the cytokines involved in the acute inflammatory response, interleukin (IL)-8 and vascular endothelial growth factor (VEGF) are the main mediators of leukocyte activation and vascular capillary response to inflammation, respectively [12][13][14], whereas transforming growth factor (TGF)-b1 and fibroblast growth factor (FGF) are involved in the activation of fibroblasts to produce and deposit collagen [15,16].…”

New agents for pleurodesis

“…Our studies on both rabbits [27] and sheep [28,29] revealed that intrapleural injection of small amounts of TGF-β results in better pleurodesis than does the intrapleural injection of either doxycycline or talc slurry. Pleurodesis occurs faster after TGF-β than after talc [30].…”

“…Pleurodesis occurs faster after TGF-β than after talc [30]. Moreover, the pleural fluid that results from intrapleural injection of TGF-β is characterized by a much lower WBC count and LDH level than the fluid that results from intrapleural injection of doxycycline or talc slurry [27]. The lower pleural fluid WBC count and LDH level suggest there is less inflammation and this might be associated with less chest pain and fever if TGF-β were injected into humans.…”

Transforming growth factor‐β induces collagen synthesis without inducing IL‐8 production in mesothelial cells

“…The pleurodesing agent was diluted to a standard volume of 2.5 mL and injected via the chest tube, followed by 1.0 mL of 0.9% NaCl solution to clear the dead space. All samples were collected by aspiration via the chest tubes 24 h after the intrapleural injections and analysed for total leukocyte counts, protein and lactate dehydrogenase (LDH) levels as described previously [11,12]. The biochemical analyses of the pleural fluid in these rabbits have been the topic of previous reports [11,12].…”

“…The discovery that direct intrapleural injection of TGF-b 2 produced pleurodesis effectively, promptly and with no short-term complications in both rabbit and sheep models [11][12][13][14] challenges the traditional concept that acute inflammation is an essential initiating event in fibrosis [15,16].…”