Abstract
BackgroundPulmonary fibrosis is a 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 cause 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. MethodsThe 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. ResultsThe 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. 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, ER stress blockade also inhibited ZC3H4 expression, indicating the positive feedback regulatory mechanism of ER stress on ZC3H4. ConclusionsOur results demonstrate that ZC3H4 and sigmar1 might act as novel therapeutic targets for silicosis, providing a reference for further pulmonary fibrosis research.
Highlights
Silicosis is a chronic occupational disease caused by exposure to dust particles containing a high level of free silica-containing silicon dioxide (SiO2), and these particles are often found in mining, quarry, metal foundries and other sandy industrial environments [1, 2]
The SiO2-enhanced fibroblast activation was attenuated by specific knockdown of ZC3H4 and inhibition of endoplasmic reticulum (ER) stress, demonstrating that ZC3H4 activated fibroblasts via the sigmar1/ER stress pathway
Our results demonstrate that ZC3H4 and sigmar1 might act as novel therapeutic targets for silicosis, providing a reference for further pulmonary fibrosis research
Summary
Silicosis is a chronic occupational disease caused by exposure to dust particles containing a high level of free silica-containing silicon dioxide (SiO2), and these particles are often found in mining, quarry, metal foundries and other sandy industrial environments [1, 2]. The deposition of silica particles in the alveoli of the lungs is the beginning of the pathophysiological process of silicosis. Silica particles ingested by lung cells induce an inflammatory response that produces large amounts of collagen and stimulates fibroblast overproliferation [7]. The principal characteristics of pulmonary fibrosis in silicosis include fibroblasts, myofibroblast proliferation, alveolar damage and deposition of extracellular matrix (ECM) components, which involve the abnormal remodeling of lung structure and an irreversible decline in lung function [8]. 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; 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
