Inhibition of EP300 and DDR1 synergistically alleviates pulmonary fibrosis in vitro and in vivo

• Published in: Biomedicine & pharmacotherapy Vol. 106; pp. 1727 - 1733
• Main Authors: Tao, Jia, Zhang, Min, Wen, Zhijie, Wang, Baoxue, Zhang, Lei, Ou, Yu, Tang, Xu, Yu, Xiaoping, Jiang, Qinglin
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.10.2018
• Subjects: Animals; Bleomycin; Case-Control Studies; Cell Line; Discoidin domain receptor; Discoidin Domain Receptor 1 - antagonists & inhibitors; Discoidin Domain Receptor 1 - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; E1A-Associated p300 Protein - antagonists & inhibitors; E1A-Associated p300 Protein - genetics; E1A-Associated p300 Protein - metabolism; EP300; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Fibronectins - metabolism; Humans; Idiopathic pulmonary fibrosis; Lung - drug effects; Lung - metabolism; Lung - pathology; Phosphorylation; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Rats, Sprague-Dawley; Respiratory System Agents - pharmacology; RNA Interference; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Transforming Growth Factor beta1 - pharmacology; EP300; Bleomycin; Discoidin domain receptor; Idiopathic pulmonary fibrosis
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2018.07.132

The EP300 siRNA and inhibitors sensitized DDR1 inhibitors in pulmonary fibrosis models in vitro and in vivo, implicating a combined inhibition of DDR1 with EP300 as potential therapies for IPF. [Display omitted] •Both EP300 and DDR1 were overexpressed in IPF tissues.•Overexpression of EP300 positively regulated fibronectin and DDR1, but not affected DDR1 phosphorylation.•Novel DDR1 inhibitor CQ-061 and EP300 inhibitor (or siRNA) synergistically reversed the inflammatory and fibrotic pulmonary injure.•These can be considered as potential therapeutic approach against IPF for further development. Pulmonary fibrosis is strongly correlated with inflammation factors, cytokine, and collagen secretion, whereby discoidin domain receptor 1 (DDR1) signaling plays an important role. EP300 is defined as an acetyltransferase that can acetylate histone and has been broadly studied in several chronic diseases, including cancer, inflammation and fibrosis. This study aimed to investigate the relationship between p300 and DDR1 in the pathological processes of pulmonary fibrosis. Transcriptome analysis of single cell RNA-sequencing for idiopathic pulmonary fibrosis (IPF) bronchial epithelial cells demonstrated that both DDR1 and EP300 were up-regulated and involved in the regulation of autophagy, cellular response to organonitrogen compounds, and collagen metabolic pathways, respectively. The anti-fibrotic and anti-inflammation effects of Pim1 and DDR1 inhibitors in bleomycin-induced IPF murine models were estimated. We discovered that overexpression of EP300 signaling induced MRC5 human fibroblast cells that up-regulated the expression of DDR1 and FN1; however, no effects on COL1 A1 and DDR1 phosphorylation were observed. Mechanistically, TGF-β1 activated FN1, collagen, and DDR1 signaling could be reversed by the combination of p300 siRNA and DDR1 inhibitors. Moreover, the EP300 inhibitor SGC-CBP30 displayed synergistic effects with DDR1 inhibitors in pathogenic scores, airway goblet cell counts in bronchoalveolar lavage fluid (BALF), IL-4, IFN-γ, FN1COL1 A1 secretion and α-SMA, a marker of myofibroblast. The EP300 siRNA and inhibitors sensitized DDR1 inhibitors in our pulmonary fibrosis models in vitro and in vivo, implicating a combined inhibition of DDR1 with EP300 as potential therapies for IPF.