The Contribution of the Urokinase Plasminogen Activator and the Urokinase Receptor to Pleural and Parenchymal Lung Injury and Repair: A Narrative Review

Tucker, Torry A.; Idell, Steven

doi:10.3390/ijms22031437

Cited by 13 publications

(12 citation statements)

References 98 publications

(73 reference statements)

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“…While uPAR is reported to contribute to diverse cellular functions 9 , 10 , 12 , 32 , it lacks a cytoplasmic domain that is required for intracellular signal transduction. As such, uPAR is reported to mediate signaling via interaction with other surface receptors, such as LRP1 33 .…”

Section: Discussionmentioning

confidence: 99%

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

Logan

Jeffers

Qin

et al. 2021

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 99%

“…5 B). While, the interactions between uPA and uPAR are direct and interdependent 10 , 12 , 16 , 29 , 32 , 33 , how uPAR mediates its signaling is less clear. Signaling via uPAR is reported to be mediated via interactions with multiple surface receptors, not LRP1 alone.…”

Section: Discussionmentioning

confidence: 99%

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

Logan

Jeffers

Qin

et al. 2021

Sci Rep

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“…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].…”

Section: Mesothelial Cellsmentioning

confidence: 99%

“…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.…”

Section: Mesomtmentioning

confidence: 99%

Update on Novel Targeted Therapy for Pleural Organization and Fibrosis

Tucker

Idell

2022

IJMS

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Pleural injury and subsequent loculation is characterized by acute injury, sustained inflammation and, when severe, pathologic tissue reorganization. While fibrin deposition is a normal part of the injury response, disordered fibrin turnover can promote pleural loculation and, when unresolved, fibrosis of the affected area. Within this review, we present a brief discussion of the current IPFT therapies, including scuPA, for the treatment of pathologic fibrin deposition and empyema. We also discuss endogenously expressed PAI-1 and how it may affect the efficacy of IPFT therapies. We further delineate the role of pleural mesothelial cells in the progression of pleural injury and subsequent pleural remodeling resulting from matrix deposition. We also describe how pleural mesothelial cells promote pleural fibrosis as myofibroblasts via mesomesenchymal transition. Finally, we discuss novel therapeutic targets which focus on blocking and/or reversing the myofibroblast differentiation of pleural mesothelial cells for the treatment of pleural fibrosis.

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“…We are providing additional information that multiple forms of uPA exists at these sites. 11 Each has a different proclivity of generating plasmin (►Fig. 1).…”

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confidence: 99%