Pref-1 induced lung fibroblast differentiation by hypoxia through integrin α5β1/ERK/AP-1 cascade

• Published in: European journal of pharmacology 2021-10, Vol.909, p.174385-174385, Article 174385
• Main Authors: Cheng, Wun-Hao, Lee, Kang-Yun, Yu, Ming-Chih, Chen, Jing-Yun, Lin, Chien-Huang, Chen, Bing-Chang
• Format: Article
• Language: English
• Subjects: Airway fibrosis; Animals; Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome - pathology; Biopsy; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Case-Control Studies; Cell Differentiation; Cell Hypoxia; Cell Line; Chronic obstructive asthma; Connective Tissue Growth Factor - metabolism; Disease Models, Animal; Female; Fibroblasts - pathology; Fibrosis; Healthy Volunteers; Humans; Hypoxia; Integrin alpha5beta1 - metabolism; Integrin receptor α5β1; Lung - cytology; Lung - pathology; MAP Kinase Signaling System; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mitogen-Activated Protein Kinase 3 - metabolism; Ovalbumin - administration & dosage; Ovalbumin - immunology; Pref-1; Transcription Factor AP-1 - metabolism; Up-Regulation
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174385

Chronic obstructive asthma is characterized by airway fibrosis. Hypoxia and connective tissue growth factor (CTGF) play important roles in airway fibrosis. Preadipocyte factor-1 (Pref-1) participates in adipocyte differentiation and liver fibrosis. Herein, we investigated the role of Pref-1 in airway fibrosis in chronic obstructive asthma. We found that Pref-1 was overexpressed in lung tissues from chronic obstructive asthma patients compared to normal subjects. Extracellular matrix proteins were inhibited by Pref-1 small interfering (si)RNA in airway fibroblasts from chronic obstructive asthma patients. Furthermore, ovalbumin induced prominent Pref-1 expression and fibronectin coexpression. Hypoxia induced Pref-1 upregulation and its release into medium of WI-38 cells. Hypoxia-induced CTGF expression was inhibited by Pref-1 siRNA. We also found that Pref-1-stimulated fibrotic protein expressions were reduced by ATN-161, curcumin, U0126, and c-Jun siRNA in WI-38. Furthermore, ATN161 inhibited Pref-1-induced ERK phosphorylation, and ITGA5 siRNA inhibited c-Jun phosphorylation. Moreover, expression of CTGF, Fibronectin, α-SMA, and ERK and c-Jun phosphorylation were all increased in fibroblasts from patients with chronic obstructive asthma. Taken together, these results suggest that Pref-1 participates in airway fibrosis and hypoxia-induced CTGF expression via the integrin receptor α5β1/ERK/AP-1 pathway. •Pref-1 is associated with hypoxia-induced lung fibroblasts differentiation in asthma.•Soluble Pref-1 plays an important role in lung fibroblasts differentiation.•Discovery of the signaling pathway of Pref-1-induced CTGF may help elucidate the role of Pref-1 in airway fibrosis in asthma patients.•α5β1 integrin receptor, ERK and AP-1 mediate Pref-1-induced CTGF expression in human lung fibroblasts.