TGF-ß regulation of the uPA/uPAR axis modulates mesothelial-mesenchymal transition (MesoMT).
Sci Rep
; 11(1): 21210, 2021 10 27.
Article
en En
| MEDLINE
| ID: mdl-34707211
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-ß mediated MesoMT. TGF-ß was also found to significantly induce uPA expression in PMCs undergoing MesoMT. Like uPAR, uPA downregulation blocked TGF-ß mediated MesoMT. Further, uPAR is critical for uPA mediated MesoMT. LRP1 downregulation likewise blunted TGF-ß 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Infecciones Estreptocócicas
/
Activador de Plasminógeno de Tipo Uroquinasa
/
Factor de Crecimiento Transformador beta
/
Neumonía Bacteriana
/
Receptores del Activador de Plasminógeno Tipo Uroquinasa
/
Transición Epitelial-Mesenquimal
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Sci Rep
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos