TGF-β regulation of the uPA/uPAR axis modulates mesothelial-mesenchymal transition (MesoMT)

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.

Update on Novel Targeted Therapy for Pleural Organization and Fibrosis

“…Collagen deposition and α-SMA expression also occurred by 7 day. Significant decrements in lung function and volumes were likewise observed in this model and demonstrable by 7 day [25,27,28,43,45]. The TGF-β adenoviral model is also an accepted model of pleural fibrosis.…”

“…Pleural mesothelial cells are reported to play an active role in both the initial deposition of fibrin initiated by TF and its subsequent replacement by collagen [1,23]. Pleural mesothelial cells are also reported to be a significant source of collagen in the injured pleural space [15,[24][25][26].…”

“…TGF-β is also a potent inducer of myofibroblast differentiation in diverse cell types, including lung fibroblasts and pleural mesothelial cells [24,25,[27][28][29][30][31]. Myofibroblasts appear as pleural or organizing injury in other tissues progresses.…”

“…Furthermor myofibroblast population has been shown to locally expand throughout injury in v preclinical models of pleural injury [15,36,37,40,41]. (Figure 1) [25,[27][28][29]37,43]. These newly transitioned myofibrobla pand due to increased profibrotic signaling, proliferation and resistance to apoptosis.…”

“…This population pr sively expands up to 21 day post initiation of injury. In this model, collagen depo [25,[27][28][29]37,43]. These newly transitioned myofibroblasts expand due to increased profibrotic signaling, proliferation and resistance to apoptosis.…”