Version May 2024
INTRODUCTION — The pleural space is bounded by the parietal and visceral membranes covered by a continuous layer of pleural mesothelial cells. Studies of pleural liquid dynamics in the normal pleural space are limited. Available data indicate that pleural fluid is formed from the systemic vessels of the pleural membranes at an approximate rate of 0.6 mL/h and is absorbed at a similar rate by the parietal pleural lymphatic system. Normally, the pleural spaces contain approximately 0.25 mL/kg of low protein liquid. Disturbances in either formation or absorption result in the accumulation of excess pleural fluid [1]. (See "Mechanisms of pleural liquid accumulation in disease".)
PLEURAL ANATOMY — The pleural space is a real, not potential, space that is approximately 10 to 20 micrometers wide and extends completely around the lung to the hilar root (image 1) [2-4]. The visceral pleura covers the lung and interlobar fissures; the parietal pleura covers the chest wall, diaphragm, and mediastinum. Each pleural interface has a surface area of approximately 1000 cm2. Each membrane is covered by a single cell layer of mesothelial cells and each (at least in humans and large mammals) is supplied by a systemic circulation.
The visceral and parietal pleural membranes differ in one important respect: only the parietal pleura has lymphatic stomata that open directly into the pleural space. Current concepts of pleural liquid turnover have stemmed in large part from considering the differential anatomy of the two pleural membranes [5].
Parietal pleura — The parietal pleura has been proposed as the more important pleura for pleural liquid turnover in the normal physiologic state [5]. As will be discussed in this topic, the reasons for this hypothesis lie in the proximity of the microvessels to the pleural space, the presence of the lymphatic stomata, and the consistent anatomy of the parietal pleura among species. The parietal pleural membrane overlies the intercostal fascial layer and ribs. It is approximately 30 to 40 micrometers thick, consisting of a superficial mesothelial layer and subpleural layer (picture 1) [6]. Within the subpleural layer lies loose connective tissue in which run the intercostal arteries, nerves and lymphatics. The intercostal microvessels are about 10 to 12 micrometers from the pleural space.
The most interesting and unusual features of the parietal pleura are the lymphatic stomata, holes of 2 to 6 micrometers in diameter that open onto the pleural space (picture 2) [6,7]. These measurements were obtained in the resting state; the diameters likely increase with chest expansion during inspiration. The stomata have been demonstrated on the parietal pleural surface with scanning electron microscopy. Each stoma is formed by a gap in the otherwise continuous mesothelial cell layer, where the mesothelial cells join with the endothelial cells of the lymphatics. Each lymphatic joins others, forming a lake or lacuna (picture 3); from the lacunae, collecting lymphatics join intercostal trunk lymphatics, which travel to the parasternal and periaortic lymph nodes.
The number of stomata over the parietal pleural surfaces (chest wall and mediastinum) in humans is not known with certainty. Estimates based on animal models suggest a range from 100 to 200 stomata per cm2 [6,8,9]. The distribution of stomata in some animals is nonuniform with a larger number of openings found in dependent regions [8].
By microscopy studies, including electron microscopy, these stomata have been shown to connect directly to the pleural space and to accommodate intact erythrocytes or carbon particles which have been introduced into the pleural space [6]. Using live imaging with videothoracoscopy in monkeys, researchers have been able to see carbon particles move from the pleural space into the lymphatics in the costal, mediastinal, and diaphragmatic pleura within 15 minutes and to drain to collecting lymphatics within 30 minutes [10].
Visceral pleura — The visceral pleura in humans is approximately 20 to 80 micrometers thick and consists of a mesothelial layer and a subpleural connective tissue layer (figure 1) [3,11]. The thickness varies considerably over the lung, being greatest in the caudal regions and least in the cranial regions. The subpleural connective tissue layer contains both collagen and elastin, as well as the bronchial artery capillaries and subpleural lymphatics (which do not connect to the pleural space). The alveoli and pulmonary circulation lie beneath the visceral pleural membrane. Both the bronchial microvessels and lymphatics are farther from the pleural space than in the parietal pleura (20 to 50 micrometers versus 10 to 12 micrometers, respectively).
The bronchial microvessels drain into the pulmonary veins, a feature that may have two consequences for pleural liquid formation:
●Because of the normally low pulmonary venous pressure, the bronchial arterial driving pressure is probably lower than that of other systemic microvessels, which must drain into higher pressure systemic veins. This may mean that, in the normal situation, less liquid flows from the visceral pleura than from the parietal pleura.
●When the pulmonary vascular pressures rise, the bronchial arterial driving pressure and visceral pleural liquid flow could increase resulting in transvascular filtration; pleural liquid formation could increase as a result.
Interestingly, visceral pleural anatomy differs strikingly among species of mammals. In small mammals (mice, rabbits, dogs), the visceral pleura is quite thin (5 to 10 micrometers), with almost no subpleural layer and no pleural bronchial circulation. One likely possibility for the major difference in anatomy is structural; in large mammals, the thick visceral pleura may offer necessary support for the lung tissues. The visceral pleural connective tissue may withstand and dissipate stresses in the lung, minimize overexpansion of weaker portions of lung (thereby reducing the risk of pneumothorax), and smooth out the relative expansion of different areas of lung and the distribution of ventilation.
Pleural mesothelial cell — The continuous lining cell of both pleurae is the mesothelial cell (picture 4) [3]. Not unique to the pleural space, the mesothelial cell lines the other two coelomic spaces in the body, the pericardial and peritoneal spaces. There are no differences yet described among mesothelial cells from these three locations or between the parietal and visceral locations. The mesothelial cell is a flat cell (1 to 4 micrometers thick) with a variable covering of microvilli (up to 3 micrometers long). The shape and area of the visceral mesothelial cell changes with lung inflation, with diameters that range from 27 micrometers at a transpulmonary pressure of 1.5 cm H2O to 39 micrometers at 12 cm H2O in isolated rabbit lungs [12].
Similar to that of the other two lining cell types, ie, the endothelial and epithelial cells, the mesothelial cell has been found to have many functions [13,14].
●It produces a wide array of extracellular matrix molecules and may participate in the production of the submesothelial connective tissue [15].
●The mesothelial cell, at least in vitro, is phagocytic [16,17].
●It may function as an inflammatory cell, directing movement of other inflammatory cells into the pleural space by releasing cytokines and expressing adhesion molecules [18-20]. The mesothelial cell may also recruit fibroblasts [21].
●Mesothelial cells may contribute to the balance between procoagulant and fibrinolytic activities in the pleural space [22,23].
Compared to all these known or potential functions, however, the mesothelial cell has no documented active role in liquid entry or exit from the pleural space. There is no evidence for active transport by the mesothelial cell. Furthermore, the mesothelial surface is leaky to protein and liquid, as, for example, is necessary for successful dialysis in the peritoneal space. A leaky membrane implies a passive role for the mesothelium in the movement of liquid and protein.
PLEURAL LIQUID FORMATION — Much of what we know about normal pleural liquid turnover is derived from studies in sheep, which have a pleural anatomy similar to that in humans. Studies of normal liquid turnover have been hampered by the narrowness of the pleural space and its sensitivity to inflammation. Most experiments, therefore, have relied on noninvasive studies of liquid formation, with the assumption that, in a steady-state condition, liquid will be formed and absorbed at the same rate.
Normal pleural liquid — The volume of pleural liquid is small, approximately 0.1 to 0.2 mL per kg in different species. One study in normal humans found a mean pleural fluid volume of 8.4 mL per hemithorax, or 0.26 mL per kg total [24]. The WBC count in this group of subjects was approximately 1700 per mm3, with a median differential of approximately 75 percent macrophages and 23 percent lymphocytes. The normal protein concentration of the pleural liquid is low, approximately 15 percent of the serum protein concentration.
Rate of formation — In noninvasive studies using equilibration of radiolabeled albumin from the plasma to the pleural liquid, pleural liquid in the sheep formed at 0.01 mL/kg per hour, or the equivalent of 0.6 mL/hour in a 60-kg person. This constituted a turnover rate of 11 percent of the pleural liquid volume per hour.
Origin of pleural liquid — The current consensus of pleural liquid formation is that the liquid originates from the systemic vessels of the pleural membranes, not from the pulmonary vessels [5]. In other words, pleural liquid is interstitial fluid of the systemic pleural microvessels (figure 2). There are three major considerations that support this hypothesis:
●The systemic vessels (of both parietal and visceral pleural membranes) are adjacent to the pleural space and are much closer to the pleural space than are the pulmonary vessels.
●The low pleural liquid protein concentration (1 g/dL) and ratio to the serum protein concentration (0.15 g/dL) are consistent with a filtrate from high-pressure systemic vessels. If liquid and protein are filtered at high pressure and high flow across a semipermeable membrane, large particles will be sieved and relatively restrained compared to the liquid. Thus, serum proteins, being large, will be retarded much more than the liquid in their movement across a membrane, and the protein concentration of the resultant filtrate will be low. On the other hand, if liquid and protein are filtered at low pressure and low flow, proteins are retarded less, and the protein concentration of the resultant filtrate is higher. Filtrates from low-pressure pulmonary vessels, eg, lung lymph, have a high protein concentration (4.5 g/dL) and ratio (0.7) compared to filtrates from systemic vessels and to pleural liquid.
Of note in this argument, pleural liquid formation is described as high flow, whereas its measured rate is relatively slow (0.01 mL/kg per hour). However, it is the filtration at the systemic microvessels that is described as high, or at least higher than filtration across pulmonary microvessels. Some of that filtrate is reabsorbed into the low-pressure postcapillary venules, and some is removed by bulk flow via the local lymphatic vessels. It is only the remainder that then moves into the low-pressure pleural space.
●In situations where systemic pressure varies, the pleural liquid protein concentration varies in concert. For example, systemic hypertensive rats have a lower pleural liquid protein-to-serum protein concentration ratio than do normotensive rats (0.42 versus 0.55), even though their pulmonary pressures are the same [25]. During development from the fetus to the adult, systemic blood pressure generally rises and pulmonary pressure falls. In a study in sheep, the pleural protein ratio decreased with development, as would be expected if the pleural liquid originated from the high-pressure systemic vessels [26].
Of the two pleural membranes, the parietal is thought to be more important than the visceral for normal pleural liquid formation. The arguments in favor of this view are as follows:
●The parietal pleural microvessels are closer to the pleural space (10 to 12 micrometers) than are those of the visceral pleura (20 to 50 micrometers).
●The parietal pleural microvessels probably have a higher filtration pressure than do the visceral bronchial microvessels, which are known to empty into the low-pressure pulmonary veins.
●The parietal membrane has a consistent anatomy and thickness over its extent in the body and among different species; the visceral membrane varies greatly. (See 'Pleural anatomy' above.)
●Pleural liquid formation rates are similar among species, even when the species have significantly different visceral pleural structures and circulations. Sheep, with a thick visceral pleura with a systemic blood supply, have similar pleural liquid formation rates as do dogs and rabbits, which have similar parietal pleural anatomy as sheep, but have very different visceral pleural anatomy (picture 5). If the bronchial circulation of the thick visceral pleura in sheep did contribute, one would expect the liquid formation rate of sheep to be higher than either of the other two species.
The formation of pleural liquid is dependent upon a balance of hydrostatic pressures (microvascular minus pleural) opposed by the counterbalancing osmotic pressures (microvascular minus pleural). These pressures can be quantified by application of Starling's equation. A balance of pressures has been proposed that estimates an average 14 cm H2O driving pressure for movement of liquid into the pleural space from the parietal pleura versus 9 cm H2O from the visceral pleura [5].
Alterations of the balance that could increase pleural liquid formation include: an elevation of systemic microvascular pressure (eg, from systemic venous hypertension), a decrease in pleural pressure (eg, in atelectasis), or a decrease in serum protein concentration (eg, with hypoproteinemia). Another possibility, an increase in pleural liquid protein concentration, is probably not relevant clinically. The alteration in balance would presumably be transient and followed by a new balance at a different combination of hydrostatic and countering osmotic pressures. (See "Mechanisms of pleural liquid accumulation in disease".)
PLEURAL LIQUID ABSORPTION — Because the normal situation is a steady state, the absorption rate of pleural liquid should equal the formation rate. If excess liquid is introduced into the pleural space, however, the rate of absorption increases several-fold, from the baseline rate of 0.01 to 0.02 mL/kg per hour to 0.22 to 0.28 mL/kg per hour [27,28].
The route of exit of the pleural liquid has been debated, in part because of the difficulty studying the pleural space. Various proposals have included reabsorption by the mesothelial cells themselves and passive flow of pleural liquid into the "low" pressure interstitial tissues of the lung. Nonetheless, current evidence supports the conclusion that the liquid exits the pleural space via the lymphatic stomata of the parietal pleura (picture 2) [28]. This conclusion is based upon knowledge of the physical forces operating at the pleural tissue and the evidence for bulk flow as opposed to diffusion.
Physical forces — Our current understanding of the physical forces operating at the pleural spaces do not support an important role for active transport or uptake by capillaries in the absorption of pleural liquid.
●The pleural pressure is lower than the interstitial pressure of either of the pleural tissues. With this pressure difference, a gradient of pressure directs liquid movement into but not out of the pleural space.
●The pleural membranes are leaky, offering little resistance to the movement of liquid and protein [29], as has been shown for peritoneal mesothelium [30]. Such a condition favors the passive movement of liquid, proteins, and other molecules. This is the underlying characteristic that allows for successful dialysis across the peritoneal membranes.
●Mesothelial cells have not been shown to generate an electric potential difference, which would be expected if mesothelial cells moved ions by active transport. Although pleural liquid has been reported to be alkaline with a higher bicarbonate concentration than plasma, there is no evidence yet for mesothelial participation in generating a bicarbonate gradient. Furthermore, it is difficult to explain how the mesothelium could maintain a transport gradient since it is a leaky membrane. Another explanation for ionic differences across a semipermeable membrane is by the passive distribution of ions in response to a difference in protein concentration (a "Donnan equilibrium") [31].
Evidence for bulk flow — The majority of liquid appears to exit the pleural space by bulk flow, not by diffusion. At least four findings underlie this assertion.
●Pleural liquid protein concentration does not change as a hydrothorax is absorbed [28]. With bulk flow, liquid and protein are removed together, and the protein concentration of the liquid remaining in the pleural space does not change. With diffusion, however, proteins would diffuse at a slower rate than the liquid, resulting in a progressive increase in protein concentration.
●The absorption rates of pleural liquid are constant despite differences in protein concentration [27]. If diffusion were predominant, the presence of protein would be expected to slow the removal of the pleural liquid because the higher protein osmotic pressure would reduce the pressure gradient for flow out of the pleural space.
●Absorption rates are constant despite changes in pleural liquid volume, at least once the liquid volume rises above some threshold [28]. If diffusion were the predominant mechanism of absorption, the absorption rate would be expected to change with pleural liquid volume, as the pleural liquid pressure gradient changed.
●Erythrocytes are absorbed intact from the pleural space and at nearly the same rate as the liquid and protein. This relatively free exit of erythrocytes from the pleural space indicates that the major route of exit is via holes large enough to accommodate erythrocytes (6 to 8 micrometers for the sheep erythrocytes used in the study). The only possible route then is via the parietal pleural stomata (2 to 10 micrometers) and the lymphatics.
LYMPHATIC FLOW — Lymphatic flow is influenced both by intrinsic contractility of the lymph vessels and by extrinsic respiratory movements [32]. Intrinsic contractility could potentially be altered by hormones, cytokines, or adrenergic stimulation. Respiratory movements may assist lymphatic flow by applying an alternating pressure on the subpleural lymphatics or by expanding and contracting the openings of the lymphatic stomata. Respiratory movements also promote a continuous intrapleural circulation of pleural liquid, which may favor delivery of pleural liquid to the stomata [33,34].
SUMMARY AND RECOMMENDATIONS
●The pleural space is bounded by the parietal and visceral membranes covered by a continuous layer of pleural mesothelial cells. (See 'Introduction' above.)
●The parietal pleura appears to be the more important pleural surface for pleural liquid turnover in the normal physiologic state [5]. This is suggested by several observations about the parietal pleura: parietal microvessels are closer to the pleural surface, lymphatic stomata are found on the parietal pleura, and the parietal pleura has a consistent anatomy among species. (See 'Parietal pleura' above.)
●The mesothelial cell is phagocytic, may function as an inflammatory cell, and produces a wide array of extracellular matrix molecules. These mesothelial lining cells may participate in the production of the submesothelial connective tissue. (See 'Pleural mesothelial cell' above.)
●Normal pleural liquid originates mainly from the systemic vessels of the pleural membranes, not from the pulmonary vessels. (See 'Pleural liquid formation' above.)
●Pleural liquid exits the pleural space mainly via the lymphatic stomata of the parietal pleura. (See 'Pleural liquid absorption' above.)
●Lymphatic flow draining the pleural space is influenced by both intrinsic contractility of the lymph vessels and extrinsic respiratory movements. (See 'Lymphatic flow' above.)
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