© 2002 American Thoracic Society
Fibrinolysis in the Pleural SpaceBreaking the Bonds That BindIndiana University School of Medicine Indianapolis, Indiana In 1901, Sir William Osler, the father of modern medicine, noting that pneumonia remained the most widespread and fatal of all infectious diseases, recognized the increased mortality rates associated with untreated empyema. He described the accumulation of viscous material in the pleural space as he urged the recognition that empyema should be treated as an ordinary abscess, by incision and drainage (1). The development of intrapleural loculations and fibrinous coagulum that occurs during the course of empyema has been the focus of several therapeutic manipulations in the pleural space (2). These include mechanical drainage of the pleural space to remove the procoagulant proteinaceous material as well as a more recent interest in the use of fibrinolytics (3, 4). A parapneumonic effusion is a dynamic, evolving process with free-flowing fluid early in the course of the disease, which when untreated moves on to the presence of fibrinopurulent loculations and the eventual development of a thick, fibrous pleural peel (5). There is significant controversy about the management of complicated parapneumonic effusions. The use of fibrinolytics affords lysis of the fibrin strands, while surgery with mechanical decortication via thoracoscopic techniques or open thoracotomy remains a viable option (6). The use of intrapleural fibrinolytics is complicated by the need for repeated applications and the lack of specificity of the agent used. The ideal fibrinolytic agent should be able to dissolve local fibrin clots, with a single application and without systemic side effects. An article by Idell and coworkers (7), published in this issue of AJRCCM (pp. 920–926), directly addresses this matter. The authors demonstrate that only one dose of single-chain urokinase plasminogen activator, alone or bound to its receptor, decreases the presence of adhesions between the visceral and parietal pleura in rabbit pleural spaces and in a model of tetracycline-induced pleural fibrosis. In in vitro studies, they demonstrate that recombinant human single-chain urokinase was effective in causing fibrinolysis of clots in the presence of pleural fluids from rabbits challenged with intrapleural tetracycline. The uniqueness of the use of single-chain urokinase as a fibrinolytic agent is based on scientific rationale. The present day fibrinolytics that have been extensively studied include urokinase and streptokinase. They do not discriminate between free and fibrin-bound plasminogen. Single-chain urokinase preferentially activates plasminogen bound to the fibrin polymer, which is then turned into fibrin degradation products. It causes selective and focused lysis of fibrin strands that connect the visceral and parietal pleural surfaces. The pleural membrane is covered by a monolayer of mesothelial cells that are dynamically active and express urokinase plasminogen activator receptor. The presence of this receptor is upregulated during the process of inflammation. Because single-chain urokinase binds to its receptor on the surface of the pleural mesothelium, it is relatively resistant to the action of the soluble degradative enzyme, plasminogen activator inhibitor. Thus, the increased effectiveness of this compound may relate to site-directed fibrinolysis and persistence of the lytic agent at that particular site. The apical surface of the mesothelium is particularly rich in receptors for plasminogen activators (8). There are arguments both for and against the animal model of tetracycline-induced pleural effusion and fibrosis used in the present study. The intravenous form of tetracycline hydrochloride, with a pH in the range of 3.3 to 3.5, has long been recognized as a sclerotic agent and has been used in the past for pleurodesis. The formation of exuberant fibrinous adhesions between the visceral and parietal surfaces is the key response to the drug when given intrapleurally (9). However, the model of tetracycline-induced pleural fibrosis may not reflect the pleural pathophysiology during the evolution of an empyema. The development of fibrin clots may have a different pathogenesis. In parapneumonic effusions or empyema, the inciting agent, the organism, or its products such as lipopolysaccharide from the cell wall may persist in the pleural space, leading to continuous stimulation and cycling of the process of inflammation. Thus, the responses seen in an animal model of bacterial or other infections may differ from those seen in the tetracycline model. In favor of the model used by the authors, however, it must be recognized that the formation of a fibrin clot is the final common pathway through which pleural fibrosis develops, irrespective of the inciting agent. Interestingly, dissolution of fibrin in the treated group of animals was obtained via a single dose of the fibrinolytic agent. This represents a significant advance over techniques used today, where both streptokinase and urokinase require several days of therapy to achieve effectiveness. The present investigation addresses the need for the development of better fibrinolytic agents that are specific to plasminogen absorbed onto fibrin clots, act locally at the site without systemic effects, and are effective with a single dose. It appears that the authors have been responsive to this challenge and have opened the door to further investigation of effective fibrinolytic management of complicated parapneumonic effusions. REFERENCES
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