Both visceral and parietal pleurae in humans are approximately 40 μm thick. Between the pleural surface and underlying tissue, five layers are identified histologically, consisting of a single cellular layer and four subcellular layers (Fig. 53.3), as follows:

Mesothelial Cells: Mesothelial cell is the predominant cell type in the pleural cavity. They vary from flat to cuboidal and can range from 10 to 50 μm in diameter and from 1 to >4 μm in thickness. Mesothelial cells are adherent to one another at the apical surface via tight junctions. At the basal surface, the cells are more loosely associated, although the basal portions are often seen to overlap. The cells slide over one another during the respiratory cycle, and therefore, at full inspiration the overlap disappears completely.

The pleural cavity is frequently invaded by undesirable agents, but the pleural cavity is not under close surveillance by polymorphonuclear cells. Mesothelial cells thus provide the frontline defense against invading cells (e.g., cancer), pathogens (e.g., bacteria), and particular matters (e.g., asbestos) by provoking a significant inflammatory response, phagocytosis, and release of potent cytokines which effectively recruit inflammatory cells (e.g., neutrophils) to initiate appropriate immune responses to eradicate the invading molecules. Mesothelial cells are multipotent and have definite roles in extracellular matrix synthesis and hence pleural fibrosis and repair. The diverse range of biological functions mesothelial cells play in both health and disease states is reviewed elsewhere.

A diverse range of insults can affect the pleura, and the resultant responses are equally complex. Most pleural disorders, however, involve inflammatory changes, fibrosis, and often vascular hyperpermeability, leading to fluid accumulation. Detailed discussion on pleural pathologies can be found in specialist texts.

Pleural Inflammation and Fibrosis: Acute pleuritis develops with many pleural diseases (e.g., infection) as well as iatrogenic procedures (e.g., pleurodesis), and if persists, the chronic inflammation often progresses to pleural fibrosis and thickening (e.g., asbestos-related fibrothorax) (Fig. 53.4). In addition to fibroblasts, mesothelial cells also contribute to collagen and matrix synthesis in pleural fibrosis. Mesothelial cells can undergo epithelial-mesenchymal transformation and convert into fibroblast-like cells, a process implicated in peritoneal fibrosis. For detailed review of the causes and pathology of pleural fibrosis, please refer to reviews elsewhere.

Pleural Effusion: The development of pleural effusions is further discussed below.

Pleural Malignancy: An estimated 300,000 patients develop a malignant pleural effusion per annum in the USA, which can arise from metastatic or primary pleural cancers. Metastatic pleural disease accounts for the majority of cases (Fig. 53.5a) with lung and breast being the most common primary cancer sites. In Europe, one million patients with lung cancer develop a pleural effusion each year. Cancer cells embolize to peripheral lung tissues and/or directly invade the visceral pleura before spreading onto the parietal surface. Occasionally, hematogenous or direct spread to the parietal pleura can occur. In contrast, primary pleural mesothelioma (Fig. 53.5b) is believed to originate from the parietal pleura before spreading to the visceral pleura. Mesothelioma patients with disease limited to the parietal, but not the visceral, pleura have been shown to have better prognosis (33 vs. 7 months). Figure 53.6 shows an example of the histological appearance of a malignant pleural mesothelioma.

The importance of pleural involvement in non-small cell lung cancer has been recognized in the latest (7th edition) revised “TNM classification of malignant tumors”; the presence of a malignant pleural effusion staged the cancer at M1a (stage IV), reflecting the advanced (and inoperable) nature of the disease when the pleura is involved. A series of studies have shown that positive pleural lavage cytology for malignant cells is a poor prognostic indicator in patients undergoing resection of lung cancer, with a median survival of 13 months compared to 49 months if negative. The importance of pleural lavage cytology has recently been emphasized in a meta-analysis. Currently, results of pleural lavage are not part of the TNM staging system. However, a new classification of visceral pleural invasion (VPI), PL0-3, has been proposed and is now in use in many centers:

Breaching the elastic layer of the visceral pleural layer, PL1 and 2, confers VPI and a T status of pT2. Five of the six studies using this staging system showed adverse prognosis for patients with VPI. Parietal involvement is termed pT3.

Pleural malignancies often express high levels of vascular endothelial growth factor (VEGF), which in animal studies is a key driving force for pleural/peritoneal fluid formation. The role of antagonizing VEGF to control malignant effusions has not been established.

Pneumothorax: Stretched out visceral pleura in the statically expanded lung apices is prone to bleb and bullae formation, even in nonsmoking individuals. These are thought to be an important factor in predisposition to primary spontaneous pneumothorax. A recent study of primary pneumothorax using fluorescein-enhanced autofluorescence thoracoscopy raises the possibility of diffuse leak from the visceral surface (“pleural porosity”) rather than one ruptured bleb as the source of air leak from the lung.

Due to the anatomical boundaries of the parietal pleura, iatrogenic pneumothorax may result from insertion of subclavian central venous catheters, damaging the pleura above the first rib. Due to pleural extension below the costal margin inferiorly, pneumothorax may occur during attempted posterior access to upper abdominal organs.

The pleura permits friction-free movement of the lungs within the relatively rigid thorax and facilitates the development of positive and negative intrapleural pressure during the respiratory cycle. A patent pleural cavity is, however, not essential to life. Longitudinal studies of patients who underwent talc pleurodesis to obliterate the pleural space as treatment for pneumothoraces showed minimal restrictive changes in lung functions after 22–35 years. This was collaborated by animal studies which showed no major impairment in lung volumes and gaseous exchange following pleurodesis. Studies of elephants showed that many were autopleurodesed at birth, and their pleural cavity is replaced by fibrous tissues. It is intriguing why humans, throughout evolution, maintain a patent pleural cavity that is nonessential and susceptible to numerous disease pathologies.

In the healthy state, the pleural cavity contains a small amount of normal physiologic fluid to facilitate the gliding of the visceral pleura over the parietal pleural membrane. This pleural fluid is formed by filtration, according to the net hydrostatic-oncotic pressure gradient, from the systemic, especially the intercostal arterial, circulation of parietal pleura. Water and small molecules (≤4 nm) can pass freely between the mesothelial cells, whereas transcytosis can allow active transport of larger particles through the mesothelial cells.

There is approximately 0.13  ±  0.06 mL/kg body mass of normal physiologic fluid in each hemithorax as estimated by the urea dilution method in a pleural lavage study of normal subjects undergoing thoracoscopy. The fluid is a transudate with low protein and lactate dehydrogenase (LDH), and its biochemical composition (e.g., glucose and urea concentrations) resembles that of other interstitial fluids. Total leukocyte counts average 1,716 cells/μL, which are predominantly (75%) macrophages and lymphocytes (23%) in nonsmokers, but the numbers of neutrophils are significantly raised in smokers.

Extrapolating from animal data, a 70-kg man produces 17 mL/day of physiologic pleural fluid. The rate of formation approximates 0.01 (in sheep) to 0.02 (in rabbits) mL/kg/h, and the half-life of fluid turnover is 6–8 h. The drainage capacity in normal pleura is large (estimated around 0.2–0.3 mL/kg/h) and well over the usual production rates.