Fibrosis of the pleura can result from diverse processes that include infection (bacterial empyema, tuberculous pleurisy), dust exposure (asbestos), immunologic disease (rheumatoid pleurisy), and malignancy. The common thread in these pleural injuries is inflammation. The response of the mesothelial cell to injury and the maintenance of its integrity, as well as that of the basement membrane, play a pivotal role in the development of pleural fibrosis. Although fibrosis can occur in all solid organs, it can also occur in the pleural space, which does not have an inherent matrix. How does a pleural space matrix develop so that fibrosis can occur?
Pleural inflammation is virtually always associated with an exudative pleural effusion that acquires procoagulant activity. The major procoagulant following pleural injury is tissue factor, which has its origin in residual pleural cells, including mesothelial cells, macrophages, and fibroblasts. 1,2 Coagulation substrates present in pleural fluid are acted on by tissue factor and factor VIIa, with conversion of fibrinogen to fibrin, and the formation of an intrapleural neomatrix. An inhibitor to tissue factor, tissue factor pathway inhibitor (TFPI), has been found in pleural effusions, clinically and in experimental animals. 1,2 Furthermore, both tissue factor and TFPI have been documented to be elaborated by mesothelial cells and lung fibroblasts. The balance between tissue factor and TFPI appears to be important in the production and persistence of pleural fibrosis. Exudative (capillary leak) pleural effusions (empyema) express a greater upregulation of coagulability than transudative (hydrostatic) effusions (CHF) and, therefore, are more likely to develop pleural fibrosis. When intrapleural generation of tissue factor exceeds the elaboration of TFPI, the procoagulant state dominates and favors fibrin formation analogous to the pleural finding in bronchoalveolar lavage fluid in patients with adult respiratory distress syndrome. 3 Concomitantly, fibrinolysis is downregulated by the increased expression of plasminogen activator inhibitor-1 (PAI-1). 2 As pleural adhesions form between the two pleural surfaces, progressive collagen deposition can develop because of the events associated with wound healing. Thus, the pathogenesis of pleural fibrosis is characterized by disordered fibrin turnover. The findings by Wolff et al., in this issue of the journal, suggest that the duration of an exudative pleural effusion, especially if present for several months, is more likely to be associated with the presence and extent of pleural adhesions. This implies, like in the case of malignancy, that there is continuing low-grade inflammation, which over time can lead to pleural adhesions, loculation, and sometimes an entrapped lung. Although pleural adhesions are not typically seen in the persistent pleural effusion of yellow nail syndrome, it is common to see pleural fibrosis with other chronic pleural effusions such as benign asbestos pleural effusion (BAPE) and rheumatoid pleurisy. These clinical observations are logical when the degree of inflammation is considered in the aforementioned diseases.
When pleural injury occurs, the mesothelial cell plays a key role in initiating the inflammatory response. An early response is the release of chemokines from the mesothelial cell, which fosters phagocytic cell migration intrapleurally. Vascular endothelial growth factor (VEGF) is upregulated in mesothelial cells in malignancy and leads to increased vascular permeability and angiogenesis. 4,5 Recent literature has verified that VEGF is important in movement of fluid through serous membranes, both in animal models and in human empyema, tuberculosis, and malignancy. 6
The pleural inflammatory response is sustained by cellular and extracellular matrix protein mediators such as hyaluronan. Fragments of hyaluronan induced by hydrolysis emulate the inflammatory process by attracting malignant and mononuclear cells and changing the population of pleural cells when metastatic pleural effusions develop. 7 Other extracellular matrix proteins (fibronectin, types I and IV collagen) are produced by mesothelial cells and can also participate in sustaining inflammation through recruitment of inflammatory cells and maintenance of increased permeability.
Not only does the mesothelial cell initiate the inflammatory response, but it also appears to regulate the duration of the response. Mesothelial cells can regulate the apoptosis of neutrophils, monocytes, and lymphocytes by releasing factors, such as GM-CSF, which inhibits programmed cell death during pleural infection. 8 Pleural space inflammation can resolve with a normal mesothelium without remodeling or fibrosis or could result in the development of adhesions, fibrosis, and destruction of the pleural membrane. However, the precise process of pleural remodeling remains unknown. Some insight has been achieved in the study of talc pleurodesis. Intrapleural talc insufflation appears to rapidly and markedly upregulate basic fibroblastic growth factor (b-FGF)in pleural fluid, whereas in vitro, talc-stimulated mesothelial cells release b-FGF. 9 However, this process is inhibited in vitro by prevention of protein synthesis or inhibition of phagocytosis and adherence of talc to the mesothelial cell. Furthermore, in patients, there is a significant inverse correlation between the release of b-FGF into pleural fluid and tumor size, implying that pleurodesis requires normal mesothelial cells to release growth factors for fibroblasts. 10
In experimental empyema, investigators have demonstrated a positive correlation over time in the pleural fluid levels of TGF-β1 and both pleural thickness and fibroblast score. 11 TGF-β is a potent chemoattractant for fibroblasts and stimulates extracellular matrix formation. 12 TGF-β is both synthesized and secreted by the normal mesothelial cell. 13 When stimulated in vitro by TGF-β, human pleural mesothelial cells secrete PAI-1 inhibitor. 14 Furthermore, TGF-β1 has been found to be elevated in human pleural effusions that have developed fibrosis from tuberculous pleurisy 15 and has been localized in fibrotic lesions of asbestos-induced pleuropulmonary fibrosis. 16
Fibrosis will occur in the lung or in the pleural space if the epithelial (mesothelial) integrity is destroyed and the balance of fibrin turnover favors coagulation over fibrinolysis. The extent of vascular permeability and the balance between angiogenesis and angiostasis are also important factors that will determine the completeness of resolution or the degree of fibrosis following pleural injury.
The findings of Wolff and colleagues that the number and frequency of thoracentesis were not related to pleural adhesion formation is congruous with the current concepts of pleural fibrosis. The development of pleural fibrosis requires a persistent inflammatory response and not a transient, minor insult. It appears that it is not the duration of the effusion that is important in the development of pleural fibrosis, but the perpetuation of the pleural inflammation, because the transudate congestive heart failure and the exudate yellow nail syndrome do not develop pleural adhesions or fibrosis whereas patients with malignancy, rheumatoid pleurisy, and parapneumonic effusions (that have delayed treatment) commonly result in impaired wound healing.
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