scholarly journals PBI-4050 Reduces Pulmonary Fibroblast Activation, Proliferation, and AKT/mTORC/4E-BP1 Signaling

L. Gagnon ◽  
M. Leduc ◽  
M.J. Nsaibia ◽  
J. Ouboudinar ◽  
C. Shimbori ◽  
2020 ◽  
Hammad Ghafoor ◽  
Han Chu ◽  
Jie Huang ◽  
Menglin Chen ◽  
Zhangyan Wang ◽  

Abstract Background Pulmonary fibrosis is the sequela of many pulmonary diseases, such as pneumoconiosis and idiopathic pulmonary fibrosis. The principal characteristics of pulmonary fibrosis comprise myofibroblast proliferation, alveolar damage and deposition of extracellular matrix components, which causes abnormal lung structure remodeling and an irreversible decline in lung function; however, the detailed mechanisms remain unclear. The current study focused on the role of ZC3H4, a new member of the zinc finger protein family, in SiO2-induced pulmonary fibrosis. Methods The expression of ZC3H4 and fibroblast activation markers (COL1A1, COL3A1 and ACTA1) was measured by western blotting and immunofluorescence staining after SiO2 exposure (50 µg/cm2). The functional change in fibroblasts was studied with a scratch assay and a 3D migration assay. The CRISPR/Cas9 system was used to explore the regulatory mechanisms of ZC3H4 in pulmonary fibroblast cells. Results The expression levels of ZC3H4 and sigmar1 (a key regulator of ER stress) were increased in pulmonary fibroblast cells and were associated with fibroblast activation, as indicated by the increase in COL1A1, COL3A1 and ACTA1, as well as the migration ability. The SiO2-enhanced fibroblast activation was attenuated by specific knockdown of ZC3H4 and inhibition of ER stress, demonstrating that ZC3H4 activated fibroblasts via the sigmar1/ER stress pathway. Interestingly, an ER stress blockade also inhibited ZC3H4 expression, indicating the positive feedback regulatory mechanism of ER stress on ZC3H4. Conclusions Our results demonstrate that ZC3H4 and sigmar1 might act as novel therapeutic targets for silicosis, providing a reference for further pulmonary fibrosis research.

2016 ◽  
Vol 151 (1) ◽  
pp. 126-138 ◽  
Xingang Wang ◽  
Yuxia Zhang ◽  
Wei Zhang ◽  
Haijun Liu ◽  
Zewei Zhou ◽  

1987 ◽  
Vol 82 (3-4) ◽  
pp. 298-301 ◽  
Leif Bjermer ◽  
Anna Engström-Laurent ◽  
Martin Thunell ◽  
Roger Hällgren

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