title: Tissue plasminogen activator potently stimulates pleural effusion via a monocyte chemotactic protein-1-dependent mechanism.
abstract: Pleural infection is common. Evacuation of infected pleural fluid is essential for successful treatment, but it is often difficult because of adhesions/loculations within the effusion and the viscosity of the fluid. Intrapleural delivery of tissue plasminogen activator (tPA) (to break the adhesions) and deoxyribonuclease (DNase) (to reduce fluid viscosity) has recently been shown to improve clinical outcomes in a large randomized study of pleural infection. Clinical studies of intrapleural fibrinolytic therapy have consistently shown subsequent production of large effusions, the mechanism(s) of which are unknown. We aimed to determine the mechanism by which tPA induces exudative fluid formation. Intrapleural tPA, with or without DNase, significantly induced pleural fluid accumulation in CD1 mice (tPA alone: median [interquartile range], 53.5 [30-355] μl) compared with DNase alone or vehicle controls (both, 0.0 [0.0-0.0] μl) after 6 hours. Fluid induction was reproduced after intrapleural delivery of streptokinase and urokinase, indicating a class effect. Pleural fluid monocyte chemotactic protein (MCP)-1 levels strongly correlated with effusion volume (r = 0.7302; P = 0.003), and were significantly higher than MCP-1 levels in corresponding sera. Mice treated with anti-MCP-1 antibody (P < 0.0001) or MCP-1 receptor antagonist (P = 0.0049) demonstrated a significant decrease in tPA-induced pleural fluid formation (by up to 85%). Our data implicate MCP-1 as the key molecule governing tPA-induced fluid accumulation. The role of MCP-1 in the development of other exudative effusions warrants examination.
authors.affiliation: 1 Pleural Disease Unit, Lung Institute of Western Australia, Perth, Western Australia, Australia.
authors.forename: Sally M
authors.initials: SM
authors.lastname: Lansley
authors.affiliation: 1 Pleural Disease Unit, Lung Institute of Western Australia, Perth, Western Australia, Australia.|2 School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia; and.
authors.forename: Hui Min
authors.initials: HM
authors.lastname: Cheah
authors.affiliation: 1 Pleural Disease Unit, Lung Institute of Western Australia, Perth, Western Australia, Australia.
authors.forename: Julius F
authors.initials: JF
authors.lastname: Varano Della Vergiliana
authors.affiliation: 2 School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia; and.|Departments of 3 Renal Medicine and.
authors.forename: Aron
authors.initials: A
authors.lastname: Chakera
authors.affiliation: 1 Pleural Disease Unit, Lung Institute of Western Australia, Perth, Western Australia, Australia.|2 School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia; and.|4 Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
authors.forename: Y C Gary
authors.initials: YC
authors.lastname: Lee
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D035422:Pleural Cavity / Q000378:metabolism / Q000473:pathology; D010996:Pleural Effusion / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000378:metabolism* / Q000633:toxicity
chemical_list: C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D010959:Tissue Plasminogen Activator
keywords: effusion; intrapleural fibrinolytic therapy; monocyte chemotactic protein-1; pleural infection; tissue plasminogen activator