 2 Produces an Excellent Pleurodesis in Rabbits
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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of the present study was to determine whether the
intrapleural injection of transforming growth factor 
2 (TGF-2) would produce a pleurodesis in rabbits. Single intrapleural injections of TGF-2 at doses of 5.00 µg (n = 12), 1.67 µg (n = 10), 0.50 µg (n = 10), or 0.167 µg (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-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 µg
of TGF-2 and buffer alone, respectively. Intrapleural injection of
the larger doses of TGF-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-2 induces pleurodesis in a dose-dependent manner. A dose of 5.0 µg produced satisfactory pleurodesis in almost all of the rabbits so treated. Larger
doses of TGF-2 induced larger pleural effusions with relatively low
pleural fluid WBC counts and LDH levels. The ability of TGF- to
produce a pleurodesis in patients with recurrent pleural effusions or
pneumothorax should be investigated. A single intrapleural injection of TGF-2 may produce a pleurodesis both safely and painlessly.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The treatment of recurrent pleural effusion or recurrent pneumothorax frequently involves the creation of a pleurodesis. With a pleurodesis, fusion of the visceral and parietal pleurae occurs, leaving no space for the collection of pleural fluid or air. In clinical practice, a pleurodesis is most commonly created by injecting a sclerosing agent through a chest tube. The agents most commonly used are antineoplastic drugs (bleomycin, mitoxantrone, or nitrogen mustard), tetracycline derivatives (doxycycline or minocycline), or talc slurry. None is ideal. Bleomycin is relatively expensive (~ $1,000/patient) and is probably less efficacious than are the tetracycline derivatives or talc (1). The injection of the tetracycline derivatives is at times extremely painful (2). The injection of talc can lead to the development of acute respiratory distress syndrome and death (3, 4). Accordingly, the search continues for an ideal sclerosing agent.
The exact mechanisms responsible for pleurodesis are unknown. It is thought that the intrapleural injection of an irritant produces inflammation (5), which in turn initiates a cascade of events that culminates at times in the creation of a pleurodesis. Cytokines are unquestionably involved in the processes that result in pleurodesis. Theoretically, it might be possible to create a pleurodesis by the intrapleural injection of a cytokine, which would avoid the need for injury to the pleura.
If a solitary cytokine could produce a pleurodesis, the following characteristics of transforming growth factor (TGF-) make it a good candidate cytokine for this purpose: (1) TGF- is a potent fibrogenic cytokine that regulates extracellular matrix (ECM) production; in situations in which there is too
much TGF-, fibrosis results (6). The transient overexpression
of TGF- in the rat lung leads to marked pleural and interstitial fibrosis (7). (2) Once present, TGF- can induce its own
transcription (8), which suggests that a single injection may be
sufficient to induce pleurodesis. (3) Mesothelial cells express
and secrete TGF-; therefore, a single intrapleural injection of
TGF- might result in prolonged secretion of TGF-, which
could result in pleurodesis. (4) The incubation of human pleural mesothelial cells with TGF- results in secretion of increased levels of plasminogen activator inhibitor (PAI)-1 (9),
which could facilitate pleurodesis, since inhibition of the fibrinolytic system is thought to be necessary for the production
of a pleurodesis (10).
The purpose of the present study was to determine whether
the intrapleural injection of TGF- could result in a pleurodesis. We hypothesized that the intrapleural injection of TGF-
would result in a pleurodesis and would produce less inflammation than is produced by the usual agents used for pleurodesis.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The methods used were similar to those previously described in our rabbit model of pleurodesis (11). The study protocol was approved by the Animal Care Committee of the Vanderbilt University Medical Center. New Zealand white male rabbits weighing 1.5 to 2.5 kg were lightly anesthetized with ketamine hydrochloride (35 mg/kg) plus xylazine hydrochloride (5 mg/kg) intramuscularly. The thorax was prepared for aseptic surgery by shaving the right chest wall and then sterilizing it with povidone-iodine and alcohol. The rabbit was placed in the lateral decubitus position. A 0.5-cm skin incision was made at the right lateral chest wall, approximately 4 cm anterior to the spine and 2 cm above the costal margin. The parietal pleura was exposed by bluntly dissecting the muscles underlying the skin incision. The parietal pleura was then punctured. This allowed the right lung to collapse, thereby preventing damage to the lung when a catheter was inserted. A soft silastic catheter (I.D. = 1/32 in., O.D. = 1/16 in.; Dow Corning, Midland, MI) was inserted into the pleural space. In sequence, the muscles and tissues were closed with sutures. The proximal tip of the catheter was tunneled under the skin, drawn out through the skin posteriorly and superiorly between the two scapulae, and fixed to the skin with a silk suture.
The exterior end of the catheter was plugged with a stub adaptor having a Luer-lock fitting (Cole Parmer, Vernon Hill, IL). A self-sealing injection-site fitting, with a Luer lock, was then attached to the stub adaptor (Baxter Health Care Corporation, Deerfield, IL). Air or liquid could be aspirated from the pleural space by inserting an 18-gauge needle through the self-sealing plug. After the surgery, the rabbits were closely monitored for clinical evidence of pain (vocalization, tachypnea, and restlessness). The left hemithorax received no chest tube and no injection, and served as a control. The chest tubes were left in place for 24 h before any intrapleural injections were given.
The primary goal of this research was to evaluate whether pleurodesis could be produced by the intrapleural injection of TGF-. The
TGF- used for these experiments was the recombinant human TGF-2 isoform (Genzyme Corporation, Framingham, MA), which is produced in Chinese hamster ovarian cells and is formulated in a vehicle
consisting of 20 mM sodium phosphate, 130 mM sodium chloride,
15% (wt/wt) propylene glycol, and 20% (wt/wt) polyethylene glycol
400, pH 7.2. The vehicle was prepared with United States Pharmacopoeia/National Formulary-grade reagents in water for injection, and
was sterile-filtered through a 0.2-µm filter. The stability of TGF-2 in
the vehicle had previously been demonstrated (Genzyme Corporation, unpublished data). The TGF-2 concentration was determined with a sandwich-type enzyme-linked immunosorbent assay (ELISA), utilizing two monoclonal antibodies that cross-react with TGF-2 and
TGF-3. The activity of the TGF-2 was determined with a mink lung
cell (Mv1Lu) antiproliferation assay, modified from the method described by Ogawa and Seyedin (14).
Two separate studies are included in this report. The initial study
was a pilot study to determine whether the intrapleural injection of
TGF-2 could produce a pleurodesis. The second and primary study
was a dose-response study of the production of pleurodesis by single
doses of TGF-2.
Ten rabbits were included in the pilot study (Table 1). The first two
rabbits served as controls, and respectively received one and four injections of the buffer alone. Two rabbits received one and four injections,
respectively, of TGF-2 in a dose of 5 µg, two rabbits received one and
four injections of TGF-2 at 10 µg; and two rabbits received one and
four injections of TGF-2 at 10 µg. Two further rabbits received two and
three injections, respectively, of 20 µg of TGF-2. When rabbits received
multiple injections, the injections were separated by 24 h. All injections had a total volume of 2 ml, and were followed by injection of 1.0 ml of
0.9% sodium chloride to clear the dead space of the chest tube.
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In the dose-response study, rabbits received single intrapleural injections of TGF-2 in doses of 0.167 µg (n = 4), 0.50 µg (n = 10), 1.67 µg (n = 10), or 5 µg (n = 12), or received buffer alone (n = 5). The
total volume of each injection was 2 ml.
The pleural space was aspirated via the chest tube every 24 h after the initial pleural injection. The chest tube was left in place for 96 h following the initial pleural injection, or until the volume of pleural fluid aspirated over the preceding 24 h was less than 3 ml, whichever occurred later. The total volume of pleural fluid aspirated was recorded. In the pilot study, animals scheduled to have an additional intrapleural instillation had aspiration done immediately before the instillation. The levels of glucose, protein, and lactate dehydrogenase (LDH) in pleural fluid were determined with a Vitros Model 950 automated analyzer (Johnson & Johnson, Rochester, NY). The white blood cell (WBC) count in pleural fluid was made with a hemocytometer. Leukocyte differential counts were determined by manually counting 100 cells in a Wright-stained smear.
Rabbits were killed at 14 d by intravenous injection of pentobarbital via the marginal ear vein. The thorax was removed en bloc. The trachea was intubated with a small silastic catheter and the lungs were inflated with 10% formalin in phosphate buffered saline. After the inflation, the trachea was ligated with plastic ties and the entire thorax was submerged in a 10% formalin solution for at least 48 h.
Necropsy was performed by two of the investigators (D.S.C. and R.W.L.), who were blinded with regard to the treatment of each animal. Each pleural cavity was exposed by making bilateral incisions through the diaphragms and through all the ribs at the midclavicular line. In this manner, the sternum and the medial portions of the anterior ribs were removed, so that the lung and pleural cavities could be evaluated. The presence or absence of hemothorax (clotted blood in the pleural cavity), and the position of the mediastinum in each animal, were recorded.
The degree of pleurodesis observed grossly was graded according to the following scheme: 0 = normal pleural space; 1 = one to three small adhesions in the pleural space; 2 = > 3 scattered adhesions, but lung separates easily from chest wall; 3 = generalized, scattered adhesions, with areas where lung can be separated from chest wall only with difficulty; 4 = complete obliteration of pleural space by adhesion.
The degree of pleurodesis and the characteristics of the pleural
fluid after administration of 5 µg TGF- were compared with results
obtained after the intrapleural administration of 400 mg/kg talc or 10 mg/kg doxycycline, which have been reported previously (15). The
protocol that had been followed in rabbits given doxycycline and talc
was essentially identical to that which we used for our single-dose
TGF- injections.
Statistical Analysis
All data are expressed as mean ± SEM unless otherwise stated. The pleurodesis scores and the pleural fluid volume, LDH concentration, WBC counts, and differential cell counts in the different groups were compared through two-way repeated-measures analysis of variance (ANOVA). The means in the various groups were compared through use of the Student-Newman-Keuls method. If the data failed tests of normality or equal variance, the medians were compared through Kruskal-Wallis one-way ANOVA on ranks. The medians were compared through Dunn's method (Sigma Stat; Jandel Scientific, San Raphael, CA). Differences in results were considered significant when p < 0.05.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The pilot experiment showed that the intrapleural injection of
TGF-2 can produce a pleurodesis (Table 1). All rabbits that received TGF-2 intrapleurally had a pleurodesis score of 4. In contrast, the two rabbits that received one or four injections of
the buffer alone had pleurodesis scores of only 0 and 1, respectively. In addition, the pilot study showed that a single injection of TGF-2 at a dose of 5, 10 or 20 µg could produce a
pleurodesis. The fibrous reaction with the higher doses was actually greater than would be ideal in producing a pleurodesis.
All of the rabbits except the one that received a single dose of
5 µg of TGF-2 had some adhesions in the contralateral pleural space. The rabbit that received four separate doses of 20 µg of TGF-2 had a fibrin ball in the peritoneal cavity, 112 ml
of straw-colored peritoneal fluid, 28 ml of bloody pleural fluid
in the right pleural space, and a pleurodesis score of 3 on the
left (control) side. Similar findings were made for the rabbit
that received three separate doses of 20 µg of TGF-2, but this
animal had no fibrin balls in the peritoneal cavity. The rabbit
that received four separate doses of 10 µg TGF-2 had no fibrin balls in the peritoneal cavity, but did have 100 ml of straw-colored peritoneal fluid, 8 ml of pleural fluid, and a pleurodesis
score of 2 on the control side. The rabbit that received a single
dose of 5 µg of TGF-2 had no pleural or peritoneal fluid and
had a pleurodesis score of 0 on the control side.
In the pilot study, the intrapleural injection of TGF-2 resulted in the formation of large amounts of pleural fluid, which was characterized by a relatively low WBC count and relatively low LDH levels (Table 1). Several of the rabbits had more than 20 ml of pleural fluid present at the 24 h time period.
In the primary study, single intrapleural injections of TGF-2
resulted in pleurodesis in a dose-dependent manner (Figure 1).
The mean pleurodesis score in the group that received 5 µg of
TGF-2 (3.6 ± 0.9) was significantly higher than the mean pleurodesis score in the groups that received 1.67 µg (2.6 ± 1.4, p = 0.045), 0.50 µg (1.5 ± 1.0, p < 0.001), of 0.167 µg (0.6 ± 0.9, p < 0.001) of TGF-2, or buffer (0.3 ± 0.1, p < 0.001). The
mean score for the group that received 1.67 µg of TGF-2 was
significantly greater than that for the group that received 0.50 µg (p = 0.012) or 0.167 µg (p = 0.003) or the buffer solution
(p < 0.001). In none of the rabbits did the mean pleurodesis
score on the left (control) side exceed 1. Since the pleurodesis
scores were very low and did not differ significantly in the control and 0.167 µg TGF-2 groups, these groups were combined
for statistical analysis of the pleural fluid results.
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In the primary study, intrapleural injection of the higher
doses of TGF-2 resulted in a high-volume pleural effusion
(Figure 2) with a low WBC (Figure 3). The fluid collected at
24 h was an exudate, in that the mean pleural fluid LDH concentration exceeded 2,000 IU (Figure 4), although the mean
protein levels at 24 h were in the 2.7 to 3.0 gm/dl range (data
not shown). At 24 h, the amount of pleural fluid was significantly (p < 0.02) greater in the groups that received the three
higher doses of TGF-2 than in the control group. The group
that received 5 µg of TGF-2 had significantly higher fluid volumes at 48 and 72 h. When the total amount of fluid (including
that obtained at autopsy) was compared in the different
groups, the mean amount of fluid was significantly greater in
the rabbits that received 5 µg of TGF-2 than in any of the
other groups (p < 0.05). The increased fluid had decreased to
less than 2 ml/d in almost all rabbits by Day 5, and none of the
rabbits had pleural fluid present at Day 14.
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Although the intrapleural injection of TGF-2 induced the
accumulation of a large amount of pleural fluid, the fluid did
not appear to be particularly inflammatory (Figures 3 and 4).
The pleural fluid WBC count and LDH level were both significantly lower in the group that received 5 µg of TGF-2 than
they were in the control group on all 3 d on which measurements were made. The differential cell counts were comparable in all groups (Table 2).
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We next compared the results of the intrapleural injection
of 5.0 µg of TGF-2 with the results of the injection of doxycycline at 10 mg/kg or talc slurry at 400 mg/kg. Although there
were no significant differences in the pleurodesis scores (Figure 5), the pleural fluid that resulted from the intrapleural injection of doxycycline and talc was much smaller in volume
(Figure 6) but was more inflammatory than that which resulted from the intrapleural injection of TGF-2 (Figures 7
and 8). At 24 h after injection, the mean pleural fluid WBC
counts after the intrapleural injection of TGF-2, talc, and
doxycycline were 830 cells/mm3, 6,430 cells/mm3, and 29,149 cells/mm3, respectively. At this same time the mean pleural
fluid LDH levels after the intrapleural injection of TGF-2,
talc, and doxycycline were 2,965 IU/dl; 26,435 IU/dl, and
29,593 IU/dl, respectively.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study demonstrates that a single intrapleural injection of TGF-2 produces an excellent pleurodesis in rabbits. This pleurodesis is at least as good as that which results
from the intrapleural injection of doxycycline at 10 mg/kg or
talc slurry at 400 mg/kg. Interestingly, the intrapleural injection of TGF-2 resulted in the production of much more pleural fluid, with a significantly lower LDH concentration and
WBC count, than did the injection of doxycycline or talc.
These observations suggest that induction of a pleurodesis by
the intrapleural injection TGF-2 might produce less injury to
the pleura than does the injection of doxycycline or talc slurry,
and therefore might produce less chest pain and systemic symptoms.
The mechanism by which various agents produce a pleurodesis is largely unknown. The initial event in the production of a pleurodesis is usually an injury to the pleura. An acute exudative pleural effusion develops within 12 h after the instillation of essentially all of the agents that are currently used for inducing pleurodesis, including talc (11), tetracycline derivatives (16), bleomycin (17), and mitoxantrone (18). Subsequently, the resolution of the pleural injury may or may not result in a pleurodesis (17).
It is likely that cytokines in the pleural space are responsible for determining whether or not a pleurodesis will result from a pleural injury. We reasoned that if this were true, then the intrapleural injection of a cytokine might produce a pleurodesis without requiring nonspecific injury to the pleura. Among
the cytokines, TGF- appears to be a promising candidate for
the production of a pleurodesis. TGF- belongs to a superfamily of polypeptide factors that control development and
tissue homeostasis in organisms from Drosophila to humans
(6). TGF- is found in inflammatory cells (especially macrophages) and platelets, and is very abundant in the cells of
the lung. TGF- stimulates ECM accumulation, is chemotactic
for fibroblasts and monocytes, and is involved in many lung
diseases in which fibrosis plays a part, including idiopathic pulmonary fibrosis (7, 19), asbestotic lung disease (20), and radiation-induced lung disease (21).
TGF- has several characteristics which suggest that it
might be an ideal agent for inducing pleurodesis. Pleurodesis
results from fibrosis, and the excessive production of TGF-
can lead to fibrosis. If rats are transfected with an adenovirus
vector expressing an active form of TGF-1, the transient overexpression of TGF- results in prolonged and severe interstitial and pleural fibrosis (7). In humans, there are at least five
polymorphisms of the TGF-1 gene. The lymphocytes of individuals of different TGF- genotypes produce varying amounts
of TGF-. In a population of lung transplant patients, individuals with the genotypes associated with higher production of
TGF- had more fibrosis in their native lung (22).
Mesothelial cells express and secrete TGF- (23). Since
TGF- induces its own transcription (8), a single intrapleural injection of TGF- could induce mesothelial cells to express
and secrete TGF-. Inhibition of the fibrinolytic pathway is
thought to be necessary for the production of a pleurodesis
(10); the incubation of human pleural mesothelial cells with
TGF- results in increased levels of PAI-1 (9), which should
inhibit the fibrinolytic system.
What is the mechanism by which the intrapleural injection
of TGF-2 produces a pleurodesis? Although most agents that
produce a pleurodesis induce a pleural injury, we speculate
that such a pleural injury is not necessary when TGF-2 is injected intrapleurally to produce a pleurodesis. In our study,
the low pleural fluid WBC count and LDH level after injection of TGF-2 suggests that the pleura was not severely injured. Rather, the intrapleural injection of TGF-2 appears to
induce mesothelial cells to produce collagen and more TGF-,
which in turn leads to the production of additional collagen.
Theoretically, it is possible that pleurodesis resulting from
the intrapleural injection of TGF-2 could represent an immune response to a non-species-specific product, since we used human TGF-2 in rabbits. We believe that this is unlikely for the
following reasons. First, the primary structure of the TGF- isoforms is remarkably conserved among mammalian species (24).
For example, there is only one amino acid difference between
human and murine TGF-1 in the activated form. Second, there
is complete interspecies cross-reactivity of TGF- isoforms with
their cognate receptors in all mammals (24). Human TGF-1,
-2, and -3 have all shown consistent biologic activity in tissue
studies in the mouse, rat, dog, rabbit, and pig. Third, the immunosuppressive aspect of TGF- makes it unlikely that the molecule would evoke a classic immune response in the host. Indeed,
it is extraordinarily difficult to raise antibody against this molecule (24). Fourth, when we injected other human proteins (tumor necrosis factor-
blocking antibody or interleukin-8) into
the pleural space, no pleurodesis resulted.
In our study, the intrapleural injection of TGF-2 led to the
production of much larger volumes of pleural fluid than did the intrapleural injection of doxycycline or talc. What is the mechanism by which the intrapleural injection of TGF-2
leads to the production of large amounts of pleural fluid? One
possibility is that TGF-2 increases the production of pleural
fluid via its induction of vascular endothelial growth factor
(VEGF). When quiescent cultures of mouse embryo-derived
cells or human lung adenocarcinoma cells are treated with
TGF-, VEGF messenger RNA and protein are induced (25).
In addition, when human synovial fibroblasts are incubated
with various cytokines, TGF- is the strongest inducer of
VEGF secretion (26). VEGF is known to markedly increase
the permeability of the vasculature (27). In some studies,
VEGF was more potent than histamine in increasing vascular
permeability (28). Therefore, if TGF- induced VEGF secretion in the pleural space, the increased levels of VEGF could
certainly lead to additional pleural fluid formation.
The present study shows that the intrapleural injection of
TGF- produces a pleurodesis, but what are the possible side
effects? Our pilot study demonstrates that repeated intrapleural injection of large doses of TGF-2 results in some degree of
pleurodesis on the contralateral side, and in the accumulation
of fibrous balls in the peritoneal cavity. In humans with multiple sclerosis who were given TGF-2 intravenously at up to 2.0 µg/kg three times a week for 4 wk, there was a mild deterioration of renal function and mild anemia, which were reversible
after the drug was discontinued (29).
What are the clinical implications of the present study?
Certainly none of the available agents for pleurodesis is ideal. The three primary agents used for pleurodesis at present are
bleomycin, talc, and the tetracycline derivatives. The only two
U.S. Food and Drug Adminstration-approved agents are bleomycin and talc. Bleomycin is expensive and is relatively ineffective as compared with other sclerosing agents (1). Also,
since it does not produce pleurodesis in animals with normal
pleurae (17, 30), bleomycin is unlikely to produce a pleurodesis in normal humans. There are significant questions about
the safety of talc. In a recent retrospective study of 89 talc
pleurodesis procedures in 78 patients, the incidence of respiratory complications or death was 33%; eight patients developed adult respiratory distress syndrome, one patient died, six
patients developed dyspnea, and three patients developed reexpansion pulmonary edema (4). The intrapleural injection of
a tetracycline derivative is at times very painful, and recent animal studies demonstrate that in rabbits it produces increases
in liver enzymes and produces tissue toxicity (31). Accordingly, there is need for an effective nontoxic agent for the production of a pleurodesis. Additional studies in humans are
necessary to delineate whether TGF-2 is such an agent.
In conclusion, the intrapleural instillation of TGF-2 in rabbits produces an excellent pleurodesis. The ability of TGF- or other cytokines to produce a pleurodesis in humans should
be evaluated. If the intrapleural injection TGF- produces a
pleurodesis without side effects, the production of a pleurodesis in this manner would certainly be preferable to producing
pleurodesis by the injection of a compound such as a tetracycline derivative, which produces a severe chemical burn; the
injection of an impure and dangerous chemical such as talc; or
the injection of an agent such as bleomycin, which is relatively
ineffective and is also expensive.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Richard W. Light, M.D., Director of Pulmonary Disease Program, Saint Thomas Hospital, P.O. Box 380 - 4220 Harding Rd., Nashville, TN 37205. E-mail: rlight98{at}yahoo.com
(Received in original form September 27, 1999 and in revised form December 22, 1999).
Acknowledgments: The authors would like to acknowledge the editorial assistance of Ms. Sheila Rupp, Dr. Paul Branca, Dr. Marcelo Vaz, Dr. Barrett Conner, and Dr. Dereje-Ayo.
Supported by the Saint Thomas Foundation, Nashville, TN, and Genzyme Corporation, Framingham, MA.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
REFERENCES
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Rogers, J. T.,
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