scholarly journals Repressive role of stabilized hypoxia inducible factor 1α expression on transforming growth factor β‐induced extracellular matrix production in lung cancer cells

2019 ◽  
Vol 110 (6) ◽  
pp. 1959-1973 ◽  
Author(s):  
Akira Ando ◽  
Naozumi Hashimoto ◽  
Koji Sakamoto ◽  
Norihito Omote ◽  
Shinichi Miyazaki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Extracellular Matrix ◽  
Growth Factor ◽  
Cancer Cells ◽  
Transforming Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Transforming Growth Factor Β ◽  
Extracellular Matrix Production ◽  
Matrix Production

scholarly journals Amplified canonical transforming growth factor-β signalling via heat shock protein 90 in pulmonary fibrosis

2016 ◽  
Vol 49 (2) ◽  
pp. 1501941 ◽  
Author(s):  
Zaneta Sibinska ◽  
Xia Tian ◽  
Martina Korfei ◽  
Baktybek Kojonazarov ◽  
Janina Susanne Kolb ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
A549 Cells ◽  
Lung Fibroblasts ◽  
Hsp90 Inhibition ◽  
Extracellular Matrix Production ◽  
Matrix Production ◽  
Β Receptor

Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of idiopathic pulmonary fibrosis (IPF), and is governed by transforming growth factor (TGF)-β/Smad signalling. We sought to define the role of heat shock protein (HSP)90 in profibrotic responses in IPF and to determine the therapeutic effects of HSP90 inhibition in a murine model of pulmonary fibrosis.We investigated the effects of HSP90 inhibition in vitro by applying 17-AAG (17-allylamino-17-demethoxygeldanamycin) to lung fibroblasts and A549 cells and in vivo by administering 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) to mice with bleomycin-induced pulmonary fibrosis.HSP90 expression was increased in (myo)fibroblasts from fibrotic human and mouse lungs compared with controls. 17-AAG inhibited TGF-β1-induced extracellular matrix production and transdifferentiation of lung fibroblasts and epithelial–mesenchymal transition of A549 cells. The antifibrotic effects were associated with TGF-β receptor disruption and inhibition of Smad2/3 activation. Co-immunoprecipitation revealed that HSP90β interacted with TGF-β receptor II and stabilised TGF-β receptors. Furthermore, 17-DMAG improved lung function and decreased fibrosis and matrix metalloproteinase activity in the lungs of bleomycin-challenged mice.In conclusion, this is the first study to demonstrate that HSP90 inhibition blocks pulmonary fibroblast activation and ameliorates bleomycin-induced pulmonary fibrosis in mice.

scholarly journals Transforming growth factor–β in tissue fibrosis

2020 ◽  
Vol 217 (3) ◽  
Author(s):  
Nikolaos G. Frangogiannis
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Cellular Targets ◽  
Extracellular Matrix Molecules ◽  
Interacting Networks

TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.

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