Abstract
Pleural fibrosis (PF) is a chronic and progressive lung disease which affects approximately 30,000 people per year in the United States. Injury and sustained inflammation of the pleural space can result in PF, restricting lung expansion and impairing oxygen exchange. During the progression of pleural injury, normal pleural mesothelial cells (PMCs) undergo a transition, termed mesothelial mesenchymal transition (MesoMT). While multiple components of the fibrinolytic pathway have been investigated in pleural remodeling and PF, the role of the urokinase type plasminogen activator receptor (uPAR) is unknown. We found that uPAR is robustly expressed by pleural mesothelial cells in PF. Downregulation of uPAR by siRNA blocked TGF-β mediated MesoMT. TGF-β was also found to significantly induce uPA expression in PMCs undergoing MesoMT. Like uPAR, uPA downregulation blocked TGF-β mediated MesoMT. Further, uPAR is critical for uPA mediated MesoMT. LRP1 downregulation likewise blunted TGF-β mediated MesoMT. These findings are consistent with in vivo analyses, which showed that uPAR knockout mice were protected from S. pneumoniae-mediated decrements in lung function and restriction. Histological assessments of pleural fibrosis including pleural thickening and α-SMA expression were likewise reduced in uPAR knockout mice compared to WT mice. These studies strongly support the concept that uPAR targeting strategies could be beneficial for the treatment of PF.
Highlights
Pleural fibrosis (PF) is a chronic and progressive lung disease, likely as a result of inflammation of the pleural space subsequent to injury or infection[1,2]
Proinflammatory mediators like tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β can induce urokinase-type plasminogen activator receptor (uPAR) expression in mesothelial and mesothelioma cells through transcriptional regulation, we found that these mediators reduce LRP1 expression[12]
We have previously reported that pleural reorganization in both human pleuritis and our mouse models of pleural fibrosis is characterized by the appearance of myofibroblasts and the accumulation of extracellular matrix proteins such as collagen 13–6,24–26
Summary
Pleural fibrosis (PF) is a chronic and progressive lung disease, likely as a result of inflammation of the pleural space subsequent to injury or infection[1,2]. PF, if advanced, results in lung restriction, dyspnea, and can cause respiratory compromise In these injury states, normal pleural mesothelial cells (PMCs) generally undergo a phenotypic change referred to as mesothelial mesenchymal transition (MesoMT). The urokinase-type plasminogen activator receptor (uPAR) is a 55-60 kDa glycoprotein that is expressed at the cellular surface of diverse cell types, including pleural mesothelial cells[9,10]. It is composed of 3 extracellular domains (D1, D2, and D3), which can be catalytically cleaved, between domains 1 and 2, by its ligand, the urokinase-type plasminogen activator (uPA) and plasmin. We showed that RAP treatment likewise increased uPAR half-life in pleural mesothelial cells (PMCs), prolonging uPA enzymatic activity (1). How these components regulate the progression of MesoMT remains unclear and to our knowledge has not been previously studied in the context of pleural remodeling
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
