Tissue plasminogen activator potently stimulates pleural effusion via a monocyte chemotactic protein-1-dependent mechanism

Copyright © 2015 by the American Thoracic Society. 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

Malignant Mesothelioma: Mechanism of Carcinogenesis

International audienceAlmost 60 years ago, malignant mesothelioma (MM) was acknowledged as a specific cancer related to the inhalation of asbestos fibers (1). Its strong association with asbestos exposure triggered the development of researches. They consisted in epidemiological studies to know the risk factors that explain MM occurrence in the population, and of experimental studies to understand MM biological development as a neoplastic disease. Since that time, MM remains a rare and highly aggressive cancer that prompts researches to better manage patients with MM and to offer efficient therapies. To achieve this goal, a solid knowledge of the mechanisms of mesothelial carcinogenesis is needed and deserves basic researches to progress. So far, our knowledge is based on pathophysiological and toxicological researches, and from biological and molecular studies using MM tissue tumor samples and cell lines from humans and experimental animals. Most experimental studies have been based on the cellular and/or animal responses to asbestos fibers, and in genetically modified mice, demonstrating the genotoxic effect of asbestos and relationship with MM induction. The development of large-scale analyses allowing global integration of the molecular networks involved in mesothelial cell transformation should increase our understanding of mesothelial carcinogenesis. In human, MM tumors appeared as heterogeneous entities, based on morphological patterns and molecular specificities including gene mutations. The recent development of high throughput methods allowed classification of MM according to their histological type, genomic and epigenomic characteristics and deregulated pathways. The aim of the present review is to propose a potential mechanism of mesothelial carcinogenesis by integrating data, underlying the mechanisms that may be shared with other types of fibres that may pose current health issue