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(Chest. 2006;130:702-709.)
© 2006 American College of Chest Physicians

Evidence of Innervation in Talc-Induced Pleural Adhesions*

Juan F. Montes, PhD; José García-Valero, PhD and Jaume Ferrer, MD

* From the Departament de Biologia Cel·lular (Drs. Montes and García-Valero), Facultat de Biologia, Universitat de Barcelona; and Servei de Pneumologia (Dr. Ferrer), Hospital General Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Correspondence to: Juan F. Montes, PhD, Departament de Biologia Cel·lular, Facultat de Biologia, Avda. Diagonal, 645, 08028 Barcelona, Spain; e-mail: jmontes{at}ub.edu

Abstract

Study objectives: To conduct a detailed morphologic and ultrastructural study of pleural adhesions following talc pleurodesis.

Methods: Talc with a main particle size of 8.36 ± 0.2 µm (mean ± SEM) and at a dose of 200 mg/kg in a 2-mL slurry was instilled via a small catheter into the pleural cavity of 10 male rabbits. Five rabbits were killed at 1 week, and five rabbits were killed at 1 month after instillation. At autopsy, after macroscopically observing the pleural cavity, adhesions were excised from opposing pleural surfaces and processed for histopathologic, immunocytochemical, and ultrastructural study.

Results: At 1 week, all adhesions examined were mesothelium-covered fibrovascular bands containing well-developed blood and lymphatic vessels establishing a structural continuity between both pleural layers. Nerves were present in adhesions from 20% of the rabbits. They consisted of a single fascicle containing 5 to 20 thin myelinated axons of various diameters (1 to 6 µm) uniformly distributed throughout the nerve section. The anatomic location of the adhesion did not appear to influence its overall morphology.

Conclusions: As early as at 1 week, adhesions are well-formed structures more resembling newly formed pleural tissue than a simple scar. Nerve fibers in pleural adhesions are reported for the first time, which suggests that these adhesions are potentially capable of conducting pain stimuli. Further studies are required in order to confirm our results in human pleural adhesions.

Key Words: adhesion • innervation • lymphangiogenesis • neovascularization • pleurodesis • talc • ultrastructure

Pleurodesis is a well-established therapeutic method for the treatment of recurrent spontaneous pneumothoraces and relapsing symptomatic pleural effusions of different etiologies.12 The goal of pleurodesis is to achieve the symphysis of visceral and parietal pleura in order to impede the accumulation of air or fluid in the pleural cavity. To date, many agents have been proposed as useful for pleurodesis, although many of them have only been tested in the experimental setting.23 For practical purposes, the two agents more commonly used for pleurodesis are talc and tetracycline. Since tetracycline is no longer available in most hospitals, talc has become the most frequently used sclerosing agent worldwide.4

The strong point of talc as a good choice for pleurodesis is its efficacy. Data from several studies567 report a high success rate of approximately 90% regardless of the dose administered. Nevertheless, there is no unanimity on the definition of pleurodesis success, but for most authors689 it is the radiologic finding that no fluid has reaccumulated in the pleural space. Although this is reasonable on a clinical basis, the mechanisms responsible for producing pleurodesis remain poorly understood.

Pioneering studies1011 demonstrated that 1 month after talc poudrage, dogs and cats showed obliteration of their pleural cavities. Bethune10 assayed talc poudrage in human patients and showed that complete pleural symphysis had been achieved 1 to 2 months after the procedure. A proposed theory from experimental studies explaining the mechanisms responsible for talc pleurodesis is as follows: talc particles activate the mesothelium, pleural macrophages and endothelium of the visceral and parietal pleura and a fibrinous exudate bridges both pleural surfaces. This exudate evolves to form a fibrin network by a process modulated by various coagulation and fibrinolytic factors12; posteriorly, stabilization of the fibrin network and increased levels of basic fibroblast growth factor13 result in fibroblast recruitment and collagen deposition in the newly formed adhesion.14

According to this theory, adhesions would be critical as the first step in keeping both pleural layers in contact and thus permitting pleural symphysis. In fact, in most experimental studies,151617 pleurodesis success is graded as a score according to the number and appearance of adhesions observed macroscopically. However, despite their clinical importance, little is known on the cellular and histologic processes underlying pleural adhesion formation. To this end, the present study was designed to ascertain, in a rabbit model, the morphologic and ultrastructural characteristics of talc-induced pleural adhesions.

Materials and Methods

Study Design and Procedures
Ten white, male, New Zealand rabbits weighing 1.5 to 2.0 kg were used in the present study. Right thoracotomy was performed at the seventh intercostal space, as previously described in detail,18 and 200 mg/kg of talc (mean ± SEM maximum diameter, 8.36 ± 0.20 µm; Distalc; Barcelona, Spain) suspended in 2 mL of endotoxin-free saline solution were instilled into the pleural cavity. This dose was chosen because 200 mg/kg is the minimum dose that produces an effective pleurodesis in this animal model.15 Two groups of five rabbits were killed with a lethal injection of pentobarbital at 1 week and 1 month after instillation, respectively. At autopsy, a total of 60 adhesions were excised from opposing surfaces of the visceral and parietal pleura, including costal, mediastinal and diaphragmatic parietal pleura. The adhesions were removed with part of the adjacent organs, and the specimens were processed for histopathologic, immunocytochemical, and ultrastructural examination. The study was approved by our Ethics Committee on Animal Experimentation.

Histopathologic Analysis
For histopathologic analysis, pleural adhesion samples were fixed in 4% paraformaldehyde in 0.1 mol/L phosphate-buffered saline solution (PBS), embedded in paraffin, and sectioned at a nominal thickness of 6 µm. Sections were then dewaxed with xylol, hydrated, and stained with hematoxylin-eosin. Examination was carried out by light field and polarizing microscopy.

Immunofluorescence
Pleural adhesion specimens were fixed in 4% paraformaldehyde in PBS for 2 h at room temperature. After washing with PBS, the samples were infiltrated with 30% sucrose at 4°C, embedded in optimum-cutting temperature compound (OCT; Miles Laboratories; Naperville, IL), quickly frozen in dry ice, and stored at – 20°C. Cryostat sections were cut at 6 µm, thaw mounted onto gelatin-coated slides, air dried, and stored desiccated at – 20°C. Sections were then incubated with a mouse anti-human platelet endothelial cell adhesion molecule-1 (PECAM-1) [Dako; Glostrup, Denmark] overnight at 4°C at 1:25 dilution. Bound monoclonal antibody was visualized by incubation with fluorescein isothiocyanate-conjugated goat anti-mouse Ig (Dako) for 1 h at room temperature. After extensive washes, sections were mounted (Fluoromount G; Electron Microscopy Science; Washington, PA) and observed with an epifluorescence microscope (Polyvar 2; Reichert-Jung; Vienna, Austria).

Transmission Electron Microscopy
Additional adhesion samples were fixed in 2% paraformaldehyde and 2.5% glutaraldehyde in PBS for 2 h at room temperature. Primary fixation was followed by postfixation with 1% osmium tetroxide in PBS for 1 h. The samples were dehydrated in acetone and embedded in Spurr resin following standard procedures. Semithin sections were stained with methylene blue and observed with an optical microscope (Polyvar 2; Reichert-Jung). Ultrathin sections were stained with uranyl acetate and Reynold’s lead citrate and examined with a transmission electron microscope (H-600 AB; Hitachi; Tokyo, Japan).

Results

All rabbit pleural adhesions examined in this study were mesothelial-covered fibrovascular bands containing well-developed blood and lymphatic vessels establishing a structural continuity between both pleural layers (Fig 1 , top, A). Myelinated nerve fibers were also present in adhesions from 20% (2 of 10 rabbits). In addition, polarized light microscopy revealed that foreign body granulomas of variable size were common histopathologic findings in most of the adhesions studied. The anatomic location of the adhesion within the pleural cavity did not appear to influence its overall morphology.


Figure 1
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  		Figure 1.. Top, A: Cross section of a pleural adhesion (pa) connecting the visceral and parietal (not seen) pleura; lp = lung parenchyma (hematoxylin-eosin, bar = 200 µm). Center, B: Semithin section of a pleural adhesion showing complete epithelialization and irregular dense connective tissue (methylene blue; bar = 20 µm). Bottom, C: Ultrastructural observation of a poorly differentiated mesothelial cell lining a pleural adhesion (bar = 0.5 µm). The overview shows a transmission electron microscopy image of a mesothelial cell-cell adhesive junction (bar = 0.25 µm).

 
Epithelialization
Light microscopy showed the surfaces of the adhesions to be covered by a continuous monolayer of flattened mesothelial cells (Fig 1, center, B). Complete epithelialization of the adhesions was already observed at 1 week after instillation. At that time, electron microscopy revealed that this newly formed mesothelium was composed of poorly differentiated cells without microvilli resting on a thin basal lamina (Fig 1, bottom, C). Mesothelial cell-cell adhesions consisted of tight junctions located at the apical part of the cells (Fig 1, bottom, C inset).

Extracellular Matrix and Cellularity
One week after talc instillation, light microscopy showed the adhesions to be composed of loose irregular collagenous connective tissue in various stages of maturity (Fig 2 , top, A). The collagen fibers were arranged in discrete bundles and were often aligned parallel to the longitudinal axis of the adhesion. The thicker collagen fibers were observed at the edges of the adhesion. By this stage, there were numerous fibroblasts among bundles of collagen fibers, and a variable number of macrophages, lymphocytes, and mast cells (Fig 2, top, A). The fibroblasts were enlarged with strongly stained cytoplasm, lax chromatin, and long cytoplasmic processes. At 1 month, the cellular content of the adhesions became sparser and included elongated spindle-shaped fibroblasts lying between thick dense bundles of collagen fibers (Fig 1, center, B). By transmission electron microscopy, collagen fibers showed numerous densely packed fibrils of uniform diameter (80 nm) that exhibited a characteristic cross-striated banding pattern with a period of 50 nm (Fig 2, bottom, B), typical of type I collagen. Long cytoplasmic processes of fibroblasts were often observed in close contact with these collagen fibrils (Fig 2, bottom, B).


Figure 2
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  		Figure 2.. Extracellular matrix. Top, A: Semithin section of a pleural adhesion showing irregular collagenous connective tissue in various stages of maturity. At 1 week, only the region beneath the mesothelium (m) has a loose appearance, containing numerous enlarged fibroblasts (methylene blue; bar = 200 µm). Bottom, B: Ultrastructural observation of a fibroblast process organizing the collagenous matrix (bar = 0.5 µm).

 
Neovascularization
As mentioned above, all the adhesions examined were well vascularized and contained both blood and lymphatic vessels (Fig 3 , top, A, and center, B). Angiogenesis and lymphangiogenesis were early events, occurring in the first week after talc instillation. By means of immunolocalization of the endothelial cell marker PECAM-1, sprouting angiogenesis was detected and blood vessels were observed stemming from both bases of the adhesions (Fig 3, bottom, C). Moreover, nonsprouting angiogenesis by intussusception was also observed in the newly formed capillary blood vessels of the adhesions. Lymphangiogenesis occurred contemporaneously with angiogenesis, and lymphatic vessels were also present at 1 week (Fig 3, center, B).


Figure 3
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  		Figure 3.. Neovascularization. Top, A, and center, B: Maturation of pleural adhesion parallelled rapid growth and high development of a vascular network, including arterioles (top, A) [hematoxylin-eosin; bar = 25 µm] and lymphatic vessels (center, B) [hematoxylin-eosin; bar = 50 µm]. Bottom, C: Immunolocalization of the endothelial cell marker PECAM-1 by indirect immunofluorescence reveals the parenchymal origin of newly formed vessels (arrows) that vascularize the pleural adhesion (ba = basis of the adhesion; lp = lung parenchyma; bar = 50 µm).

 
Newly developed vessels such as arterioles, capillaries, and venules were uniformly distributed throughout all the adhesions, including both the visceral and parietal segments. Larger blood and lymphatic vessels were commonly found at the edges of the adhesion. Newly formed vessels exhibited a normal morphologic and histologic appearance and, for example, all arterioles examined already displayed well-developed intimal, medial, and adventitial layers at 1 week after instillation (Fig 3, top, A).

Innervation
Examination of semithin sections of resin-embedded adhesion samples clearly revealed the presence of myelinated nerve fibers in adhesions from 20% (2 of 10 rabbits) [Fig 4 ]. Nerves were already observed at 1 week after instillation, and no differences in the percentage of adhesions containing nerve fibers were observed among experimental times. Thus, in both rabbits, the percentage of adhesions containing nerves was 67%. Moreover, the site of adhesion formation did not appear to influence their presence, given that nerves were observed in adhesions joining visceral pleura with either costal, diaphragmatic, or mediastinal parietal pleura.


Figure 4
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  		Figure 4.. Innervation. Top, A, and center, B: Pleural adhesion innervation resulted from the growth of nerves containing a variable number of thin myelinated axons (methylene blue; bars = 10 µm). Note the association of these nerves with both arterioles (top, A, and center, B) and mast cells (mc) [center, B]. Bottom, C: Ultrastructural observation of the proximal section of a newly formed nerve exhibiting a near-mature structure with a well-organized epineurium and endoneuria (bar = 0.5 µm).

 
In all adhesions examined, nerves consisted of a single fascicle containing 5 to 20 thin myelinated axons of various diameters (1 to 6 µm) uniformly distributed throughout the nerve section (Fig 4, top, A, and center, B). Nerves were always observed in association with blood vessels, mainly arterioles (Fig 4, top, A, and center, B), and followed a sinuous course along the longitudinal axis of the adhesion. Moreover, mast cells were frequently found in close proximity to both nerves and vascular structures (Fig 4, center, B). Morphometric evaluation of nerves revealed that both the nerve profile diameter and number of axons varied along the length of the nerve. In all cases, the magnitude of these two parameters, nerve diameter and axon number, was always greater in the parietal than in the visceral segment of the adhesion. On ultrastructural examination, nerves in adhesions showed well-developed myelinated axons with adjacent Schwann cells and surrounding epineurium (Fig 4, bottom, C).

Discussion

Classically, pleural adhesions are considered to be collagenous formations binding between visceral and parietal pleura. They are thought to develop in the pleural cavity secondary to several inflammatory stimuli, including infection, malignancy, and trauma.1920 Although they are commonly considered to play a critical role in the establishment of pleural symphysis,14 little is known about their histopathogenesis. The present study provides a detailed morphologic and ultrastructural description of talc-induced pleural adhesions in rabbits.

Although we have previously shown that pleurodesis with a high talc dose is associated with an increased risk of pulmonary talc deposition in rabbits,21 the dose used here was selected because 200 mg/kg is the minimum dose that induces an effective pleurodesis in this animal model.15 As early as 1 week after talc slurry instillation, adhesions were completely formed, showing bundles of collagen fibers, newly formed blood and lymphatic vessels, and complete epithelialization. Strikingly, the finding of nerve fibers in adhesions of 20% of the rabbits is reported for the first time.

A main result of the present study was the observation that nerve fibers, identified histologically and ultrastructurally, grow into rabbit pleural adhesions formed after the intrapleural administration of talc. Although nerve fibers have been found in murine22 and human23242526 peritoneal adhesions, to our knowledge this study is the first to report nerve growth into pleural adhesions. Our results further demonstrate that the anatomic location of the adhesion within the pleural cavity did not influence the presence of nerve fibers, given that nerves were observed in adhesions joining visceral pleura to both costal, mediastinal, and diaphragmatic parietal pleura.

After talc pleurodesis, we found the percentage of rabbits with nerve-containing pleural adhesions to be 20%. No data are available for our results to be compared with other experimental studies; however, in clinical series,23242526 between 38% and 100% of patients had peritoneal adhesions containing nerve fibers. The difference between the percentage of innervation found in the present study and those reported in clinical studies can be attributed to various factors, including biological and physiologic variations between rabbits and humans as well as anatomic differences between pleural and peritoneal cavities. Likewise, it has been reported that the growth of nerve fibers into peritoneal adhesions is dependent on the underlying disease.25 Thus, it has been shown that peritoneal adhesions from patients with malignant diseases are more likely to contain nerves than adhesions due to other conditions, including inflammatory and noninflammatory diseases.25

In all adhesions examined here, nerve fibers appeared to originate from the parietal pleura, which is mainly innervated by the internal intercostal nerves (costal pleura and peripheral part of the diaphragmatic pleura) and the phrenic nerves (central portion of the diaphragmatic pleura and mediastinal pleura).27 A recent electrophysiologic and pharmacologic study28 reported that the parietal pleural afferents were myelinated A{delta} and unmyelinated C-type nerve fibers. In this regard, the morphologic and ultrastructural characteristics of the nerve fibers here described, including the degree of myelinization (low) and axon diameter (1 to 6 µm), are totally comparable to those of A{delta} fibers.29 Although the effect of innervation on adhesion function is unknown, it is interesting to note that A{delta} fibers are pain-conducting fibers.29

The possible implication of this finding in clinical practice is unknown. In the aforementioned studies232426 on innervation of human peritoneal adhesions, the relationship between innervation and pain reported by the patients was unclear. An interesting question is whether human pleural adhesions may be innervated and, consequently, be a source of chronic pain. Although we have been unable to find any specific report on this issue, in our experience some patients with pleural diseases in which adhesions occur, such as tuberculosis or empyema, report chronic pain in their evolution. In the case of pleurodesis, pain is a frequent short-term adverse effect after pleurodesis with several agents,458 probably due to the inflammation created in the pleural space. Chronic pain, however, has scarcely been reported; it was described in up to 31% of patients undergoing videothoracoscopic treatment with pleural abrasion for primary or secondary spontaneous pneumothorax,3031 although in these cases it is difficult to know whether the pain was due to pleurodesis itself or to surgery. Regarding talc pleurodesis, to our knowledge two cases of chronic pleuritic pain have been reported.3233 However, the real incidence of chronic pain after talc pleurodesis may have been underestimated, since few studies have assessed the long-term outcome of these patients and chronic pain has never been prospectively evaluated.

With respect to the neovascularization process, our results showed the vascular growth patterns associated with pleural adhesion development to be similar to those described in inflammatory and malignant conditions.34 Indeed, sprouting and nonsprouting angiogenesis by intussusception were observed in the newly formed vessels and, at 1 week after instillation, all adhesions examined were well vascularized and contained arterioles, capillaries, venules, and lymphatics. These findings concur essentially with those of previous studies addressing this issue, since new blood vessel formation has been reported in human35 and animal3637 pleural adhesions, as well as in human2526 and animal223839 peritoneal adhesions. In any event, the pivotal role of angiogenesis in the production of pleurodesis was clearly demonstrated by Guo et al40 who, by inhibiting angiogenesis with anti-vascular endothelial growth factor antibody, reported a significant reduction in the pleurodesis score in a rabbit model.

On histopathologic analysis, all the newly formed vessels observed in the present study showed a normal histologic pattern, and morphologic abnormalities previously described in peritoneal adhesions,2536 such as medial and adventitial wall thickening, were not found. However, to our knowledge, this is the first report to demonstrate lymphatic vessel growth above visceral pleura elastic lamina following talc pleurodesis. Although the role of lymphangiogenesis in adhesion formation remains unknown, it has been pointed out that visceral pleura lymphangiogenesis above the elastic lamina may either contribute to pleural drainage during pathologic states or serve to recruit cellular effectors to sites of tissue inflammation.37 Likewise, it is interesting to note that most arterioles observed in the present study were spatially associated with nerve fibers, thus supporting similar findings obtained in human26 and murine22 peritoneal adhesions. It has been suggested that this association is a consequence of the control role played by the angiogenic process in nerve growth during adhesion formation.26

Overall, our findings provide evidence that restoration of the interrupted pleural tissue continuity resembles a regeneration, rather than a wound healing, process. Indeed, pleural repair after talc instillation is not based on the formation of a prototypical granulation tissue, since the repair process here observed was defective in the dense network of enlarged vessels.4142 Furthermore, the initial fibroblast invasion of the fibrinous bridges ends in the organization of well-vascularized and innervated connective tissue that resembles that of the undamaged pleura. Therefore, pleural adhesion is not just a scar produced as a consequence of the repair process, but a structure establishing a functional continuity between both visceral and parietal pleura.

In conclusion, the present study demonstrates that as early as 1 week after instillation, talc-induced pleural adhesions are fibrovascular bands containing well-developed blood and lymphatic vessels more resembling newly formed pleural tissue than a simple scar. Likewise, this study shows for the first time the presence of nerve fibers within pleural adhesions, thereby suggesting that these adhesions are potentially capable of conducting pain stimuli. Further studies are required to confirm our results in human pleural adhesions.

Acknowledgements

The authors thank Almudena García and the staff of Serveis Científico-Tècnics (Universitat de Barcelona) for technical assistance, and Christine O’Hara for linguistic advice.

Footnotes

Abbreviations: PBS = phosphate-buffered saline solution; PECAM-1 = platelet endothelial cell adhesion molecule-1

Supported by grants from the Fondo de Investigación Sanitaria (FIS 98/0333) and Red Respira (Instituto Carlos III, FIS RTYC-C03/11)-SEPAR.

None of the authors have any conflict interest to disclose.

Received for publication November 11, 2005. Accepted for publication March 9, 2006.

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