Endothelial Cell Protein C Receptor Deficiency Attenuates <i>Streptococcus pneumoniae–</i>induced Pleural Fibrosis

Keshava, Shiva; Magisetty, Jhansi; Tucker, Torry A.; Kujur, Weshely; Mulik, Sachin; Esmon, Charles T.; Idell, Steven; Rao, L. Vijaya Mohan; Pendurthi, Usha R.

doi:10.1165/rcmb.2020-0328oc

Cited by 10 publications

(9 citation statements)

References 60 publications

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“…In this model, greater than 90% of the α-SMA expressing myofibroblasts were mesothelial in origin [15]. Similar results were seen in the clinically relevant S. pneumonaie model of pleural injury [24,27,28,30,43,45]. However, in this model, significant changes in pleural thickening were apparent 7 days post initiation of injury and persisted up to 14 day post injury.…”

Section: Mesomtsupporting

confidence: 79%

“…As its name implies, the expression of EPCR was thought to be limited to endothelial cells. In this recent study, they found that EPCR is robustly expressed on the pleural surface of human lung tissues [30]. They also showed that EPCR deficiency reduced the progression of PF, as decrements in lung function and lung volume were improved in DOCK2 knockout mice.…”

Section: Novel Targets For Interventional Therapymentioning

confidence: 85%

“…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%

“…While TGF-β is known to induce the myofibroblast differentiation of diverse cell types including PMCs, other mediators including factor Xa, thrombin, activated protein C, plasmin and uPA are also known to induce MesoMT [15,30]. TGF-β induces mesenchymal transition of PMCs via activation of the canonical TGF-β/SMAD signaling pathway and noncanonical pathways [28,36,37,43,48].…”

Section: Mesomtmentioning

confidence: 99%

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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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Section: Mesomtsupporting

confidence: 79%

Section: Novel Targets For Interventional Therapymentioning

confidence: 85%

Section: Mesomtmentioning

confidence: 99%

Section: Mesomtmentioning

confidence: 99%

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Update on Novel Targeted Therapy for Pleural Organization and Fibrosis

Tucker

Idell

2022

IJMS

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“…Wild-type C57BL/6 (WT) mice and uPAR knockout mice (Plaur tm1Jld , 10–12 weeks of age, ≈20 g, Jackson Laboratory, Bar Harbor ME) were lightly anesthetized with isoflurane. Intrapleural inoculations (1.8 × 10 8 cfu, suspended in 0.9% saline) of Streptococcus pneumoniae ( S. pneumoniae , D39, National Collection of Type Cultures, Salisbury UK) were delivered by intrapleural injection in 150 µL saline, as previously described 5 , 6 , 20 , 21 . Amoxicillin was administered daily, for 4 days after infection.…”

Section: Methodsmentioning

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 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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