Oncotarget Volume 11 Issue 15 reported that additionally, immunoprecipitation and immunofluorescence studies in ATII cells and lung fibroblasts showed that pirfenidone inhibited the formation and nuclear translocation of the transcriptional fibrotic TGF- 1-induced phospho-SMAD3/MUC1-CT/active- -catenin complex, and consequently the SMAD-binding element activation.
This study provided also evidence of the inhibitory effect of pirfenidone on the TGF- 1-induced ATII to mesenchymal and fibroblast to myofibroblast transitions, fibroblast proliferation, and ATII and fibroblast senescence.
Dr. Beatriz Ballester from the Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain, and the CIBERES, Health Institute Carlos III, Valencia, Spain as well as Dr. Javier Milara from the Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain, the CIBERES, Health Institute Carlos III, Valencia, Spain, the Health Research Institute INCLIVA, Valencia, Spain and the Pharmacy Unit, Clinic University Hospital, Valencia, Spain said, "Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by extensive accumulation of abnormal extracellular matrix (ECM) in the lung and variable progression among patients, leading to death 3-5 years after diagnosis."
"Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by extensive accumulation of abnormal extracellular matrix (ECM) in the lung and variable progression among patients, leading to death 3-5 years after diagnosis"
- Dr. Beatriz Ballester, Department of Pharmacology, Faculty of Medicine, University of Valencia and the CIBERES, Health Institute Carlos III & Dr. Javier Milara - Department of Pharmacology, Faculty of Medicine, University of Valencia, the CIBERES, Health Institute Carlos III, the Health Research Institute INCLIVA, and the Pharmacy Unit, Clinic University Hospital
Invasive myofibroblasts in IPF lungs have multiple origins including lung resident fibroblasts or mesenchymal/myofibroblast transformations of alveolar type II epithelial cells.
Furthermore, both types of cells, fibroblasts, and ATII cells acquire senescent identities, which are able to promote lung fibrosis.
MUC1 extracellular domain contains the KL6 epitope domain, which can be shed into the lumen by proteolytic cleavage and it has been observed increased in serum, bronchoalveolar lavage fluid and lung tissue of IPF patients, serving as a potential biomarker in IPF disease.
Indeed, pirfenidone, which has been recently approved as IPF therapy, demonstrates only a reduction of the loss of lung function but is not able to reverse IPF progression.
In this study, the authors analyzed in vitro the anti-fibrotic mechanism of pirfenidone on the TGF- 1 canonical and non-canonical pathways as well as on the effects of cellular transformations such as ATII and fibroblast to myofibroblast transitions, cell senescence and fibroblast proliferation.
The Ballester/Milara Research Team concluded in their Oncotarget Research Paper, "the present study provided novel evidence of pirfenidone's inhibitory effect on TGF-β1-induced fibrotic cellular processes, through the inhibitory effects of pirfenidone on MUC1-CT phosphorylations, β-catenin activation, and formation of the nuclear complex of phospho-SMAD3/MUC1-CT/act-β-catenin and the following SBE activation."
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DOI - https://doi.org/10.18632/oncotarget.27526
Full text - https://www.oncotarget.com/article/27526/text/
Correspondence to - J. Kimble Frazer - [email protected]
Keywords - pirfenidone, idiopathic pulmonary fibrosis, MUC1, transforming growth factor beta-1, fibroblasts
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