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The lung and heart, the vital organs, have to be protected and also have to move and change volume continuously to function. For the best protection and function of the lung, the thorax is shaped almost like a bellows with the diaphragm as the moving part. Furthermore, the outer surface of the lung and the inner surface of the protective thoracic cage are covered by an elastic, serous, and lubricating membrane to form the pleural cavity. This is almost like inserting a sealed-wet and stretchable-plastic bag between the lung and the thoracic wall and diaphragm to decrease friction. The lubrication is accomplished by the facing mesothelial cells that have bushy-surface microvilli enmeshing hyaluronic acid-rich glycoproteins. The amount of fluid in the pleural cavity is regulated by the hydrostatic-osmotic pressure relationship and pleuro-lymphatic drainage. Excess fluid, large particles, and cells in the pleural cavity are removed through preformed stomas assisted by respiratory movements. The stoma is found only in the anterior lower thoracic wall and diaphragm and is like the drain of a sink. Finally, clinical and subclinical injuries of the pleura appear to occur often. Reactive mesothelial cells constantly repair the damages and keep the pleural cavity open. Without mesothelial cells, the lung cannot function properly and the pleural cavity will be quickly obliterated by fibrosis.

Bleomycin is the antineoplastic agent used most commonly for the treatment of malignant pleural effusion. It is absorbed rapidly from the pleural space and does not elicit pleurodesis in the normal rabbit pleura. Mitoxantrone is a new antineoplastic that differs from bleomycin in that it binds to membranes. Accordingly it might remain in the pleural space for a longer period and produce a pleurodesis. The objective of this project was to determine whether mitoxantrone is an effective sclerosant in an experimental model in rabbits. The following medications were instilled intrapleurally in anesthetized male rabbits: 35 mg/kg tetracycline or 0.5, 1.0, or 2.0 mg/kg mitoxantrone. The animals were killed at 28 days and the pleural spaces assessed grossly for pleurodesis and microscopically for fibrosis and inflammation. The mean degree of gross pleurodesis did not differ significantly in the rabbits that received tetracycline (3.8 +/- 0.4) and in the rabbits that received 2 mg/kg mitoxantrone (3.2 +/- 1.3). The degree of pleural and lung inflammation was significantly greater after mitoxantrone than after tetracycline, both ipsilaterally and contralaterally. The mortality after the highest dose of mitoxantrone was 50%. From this study we conclude that the intrapleural administration of mitoxantrone in rabbits can produce a pleurodesis. The histologic picture after mitoxantrone administration differs markedly from that after tetracycline injection. After mitoxantrone injection there are many more inflammatory cells present on the side that received the injection, and there is much more fibrosis and inflammation in the contralateral pleura and lung. The model of pleural fibrosis following intrapleural mitoxantrone may be useful for the study of pleural fibrosis.

Minocycline is as effective as tetracycline in inducing pleural fibrosis, but the long-term pleural changes induced by minocycline are unknown. The objective of this study was to evaluate in rabbits the evolution of the pleural changes induced by the intrapleural instillation of minocycline. Under light anesthesia, minocycline at 10 mg/kg in a total volume of 2 ml of bacteriostatic saline solution was injected into the right pleural space of 25 male rabbits. The animals were sacrificed in groups of five at 15 d and 1, 2, 4, and 6 mo. Macroscopic and microscopic examinations of the pleura were performed for evidence of pleural fibrosis and inflammation. Similarly, the underlying lung was also examined for microscopic alveolar fibrosis and inflammation. During the 6-mo observation period there was no significant change in the degree of pleural fibrosis. In contrast, microscopic pleural inflammation, alveolar fibrosis, and alveolar inflammation all decreased significantly over the observation period. In conclusion, intrapleural minocycline injection results in persistent pleural fibrosis at 6 mo. It remains to be determined whether the pleural fibrosis will persist beyond this period.

Pleuritis or pleural effusion frequently develops in patients with pneumonia or heart failure. Most of these pleural changes regress without intrapleural intervention. The detailed mechanisms of the regression of the pleural changes in humans are not well documented. We studied the parietal pleura of nine patients with lung cancer and two patients with coronary artery disease by scanning electron microscopy (SEM). All patients had neither radiographic nor gross evidence of pleural disease but all had mixed surface alterations by SEM. Focal denudation of mesothelial cells was common. Deeper injuries exposed thick and thin interweaving collagen bundles. Patchy depositions of amorphous or crystallized fibrin covered normal and damaged pleural surfaces, frequently admixed with macrophages, red blood cells, and tissue debris. Reactive mesothelial cells appeared to proliferate over the fibrin. Our findings suggest that subclinical pleural alterations occur often in patients with pulmonary or cardiac diseases and that an intact pleural surface in those patients is restored mainly by the proliferation of reactive mesothelial cells.

The two agents most commonly used for producing a pleurodesis are tetracycline and bleomycin. Tetracycline is no longer available due to more stringent requirements on the manufacturing process. The objective of this project was to determine whether bleomycin is an effective sclerosant in an experimental model in rabbits. The following medications were instilled intrapleurally in anesthetized male rabbits: tetracycline, 35 mg/kg, or bleomycin, 1.5 or 3.0 IU/kg diluted to a total volume of 1 ml with bacteriostatic saline solution. Twenty-eight days after the instillation, the animals were killed, and the pleural spaces were assessed grossly for evidence of pleurodesis and microscopically for evidence of fibrosis and inflammation. The intrapleural injection of bleomycin was ineffective in creating pleural fibrosis, either grossly or microscopically. The mean degree of gross pleurodesis in the six rabbits who received tetracycline was 2.7 +/- 1.5 (scale 0 to 4), while that in the rabbits who received the highest dose of bleomycin was 0.0 +/- 0.0. Based on this study, we recommend that bleomycin not be used as a pleural sclerosant in patients with nonneoplastic pleural disease, eg, those with pneumothorax, congestive heart failure or cirrhosis, and pleural effusion.

Rat pleural mesothelial cells (PMCs) in culture at the exponential growing phase were exposed to 5 micrograms/ml of chrysotile (CH) or crocidolite (CR) asbestos fibers: the cells and their chromosomes were studied 48 hours thereafter by light, scanning, and transmission electron microscopy (LM, SEM, TEM). PMCs phagocytized both CH and CR. Mild vacuolar cytoplasmic changes by LM and a few small surface blebbings by SEM were present, mainly in cells treated with CH. Metaphase chromosomes were well separated and retained surface details by SEM in the control group. Chromosomes were frequently entangled with, adherent to, and severed or pierced by long and thin curvilinear CH with occasional chromatin fibers threading over the partly severed asbestos. Similar chromosomal changes were much less frequently found in CR-treated cells; TEM confirmed the same findings. CH and CR have different physicochemical properties and also appear to have direct, intricate, but different interactions with chromosomes, as well as the cytoplasm, of PMCs.

The early development of a coelom, a primitive body cavity, with stretchable mesothelial cells endows the subsequently developed internal organs a great flexibility to expand, retract, and deform. In the pleural cavity, in addition, the lung is maintained in an inflated state by the mechanical coupling between the chest wall and the lung; the mesothelial cells with bush-like elongated microvilli enmesh hyaluronic acid-rich lubricants; both minimize the work of breathing. Normal mesothelial cells are fragile in the air, and their intercellular junctions are narrow but labile. The activated mesothelial cells, on the other hand, are resilient and rich in organelles and enzymes to partake in functions such as fibrinolysis, in order to maintain the patency of the pleural cavity. Fluid and electrolytes permeate freely between normal mesothelial cells; the fluid moves in and out of the pleural cavity following Starling's law, with the endothelium as the main barrier. Transudates in the pleural cavity are formed from alterations of the hydrostatic-osmotic pressure relationship, which normally keeps the pleural cavity dry. More than one factor is usually involved in the formation of exudates. Proteins, particles, and cells in the pleural exudates are removed mainly from the preformed stomas and the lymphatic lacuna present in the lower mediastinum and also in the subcostal region and portions of the diaphragm. This removal of the pleural fluid and particles by the lymphatic route is enhanced by the respiratory movements and is partly responsible for the topographic differences of the pleural pressure. Kampmeier's foci found in the location of the stomas are conglomerates of activated mesothelial and lymphoreticular cells with central capillary and lymphatic vessels. They act like tonsils to impede direct entry of undesirable materials from the pleural cavity into the chest wall and mediastinum.

Lympatics in the parietal pleura and diaphragm of rabbits and mice formed lacunas, terminal dilatations of lymphatic channels, with cribriform laminas bordering the pleural space at one end and one-way valves on the other end. The laminas consisted of a coarse mesh of connective tissue fibers covered by mesothelial cells at one side and endothelial cells at the other. At the fenestrated portions of the meshwork the basal surfaces of the 2 lining cells were closely apposed and some preformed stomas were found bridging the pleural and lymphatic spaces. No such structures were found in the visceral pleura, but similar cribriform laminas were also present in human parietal pleura at autopsy. Intrapleurally injected carbon particles reached the lacunas faster than similarly injected chicken red blood cells in living rabbits. Carbon particles appeared to pass through the closely apposed lining cells as well as the stomas but not into the intact interstitial structures. These structural and functional findings supported the observation that large particles and cells in the pleural cavity are removed only through the lymphatics and only at specific sites in the parietal pleura.