Abstract | OBJECTIVES: MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Authors | Jia Tao, Min Zhang, Zhijie Wen, Baoxue Wang, Lei Zhang, Yu Ou, Xu Tang, Xiaoping Yu, Qinglin Jiang |
Journal | Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
(Biomed Pharmacother)
Vol. 106
Pg. 1727-1733
(Oct 2018)
ISSN: 1950-6007 [Electronic] France |
PMID | 30119248
(Publication Type: Journal Article)
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Copyright | Copyright © 2018 Elsevier Masson SAS. All rights reserved. |
Chemical References |
- FN1 protein, human
- Fibronectins
- RNA, Small Interfering
- Respiratory System Agents
- TGFB1 protein, human
- Transforming Growth Factor beta1
- E1A-Associated p300 Protein
- EP300 protein, human
- Ep300 protein, rat
- DDR1 protein, human
- DDR1 protein, rat
- Discoidin Domain Receptor 1
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Topics |
- Animals
- Case-Control Studies
- Cell Line
- Discoidin Domain Receptor 1
(antagonists & inhibitors, metabolism)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Synergism
- Drug Therapy, Combination
- E1A-Associated p300 Protein
(antagonists & inhibitors, genetics, metabolism)
- Fibroblasts
(drug effects, metabolism, pathology)
- Fibronectins
(metabolism)
- Humans
- Lung
(drug effects, metabolism, pathology)
- Phosphorylation
- Pulmonary Fibrosis
(drug therapy, genetics, metabolism, pathology)
- RNA Interference
- RNA, Small Interfering
(genetics, metabolism)
- Rats, Sprague-Dawley
- Respiratory System Agents
(pharmacology)
- Transforming Growth Factor beta1
(pharmacology)
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