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  • Materials and methods br Discussion Our


    Materials and methods
    Discussion Our study revealed a positive regulatory role of EP300 in IPF. Our main findings were as follows: (a) Both EP300 and DDR1 were up-regulated in IPF patients, and their regulated pathways were closely interacted; (b) Overexpression of EP300 significantly stimulated FN1 production and DDR1 expression, but were not observed to affect COL1 A1 synthesis and DDR1 phosphorylation; (c) Combined inhibition of DDR1 and EP300 synergistically suppressed fibrotic injury both in vitro and in vivo. In summary, our results provided a novel insight into the therapeutic potential of EP300 in IPF, and the synergistic inhibition of DDR1 and EP300 may serve as a novel approach for IPF therapy. Overexpression of EP300 and DDR1 has been sporadically reported in the pathogenesis of pulmonary fibrosis and other fibrotic diseases. Zeng et al. reported that EP300 was increased in TGF-β1 treated lung fibroblasts and mediated decreases of SIRT1 expression. Bhattacharyya et al. found that both EP300 overexpression stimulated by TGF-β1 via the Egr-1 pathway and EP300 reversely enhanced Smad-dependent TGF-β signaling. Borza et al. reported that DDR1 was involved in several diseases beyond pulmonary fibrosis, including cancer, osteoarthritis, renal, liver injury, and atherosclerosis. In agreement with our previous report, we confirmed that DDR1 and EP300 overexpression in lung tissues of IPF patients may relate to the elevation of inflammation and cytokines. Furthermore, EP300 was indicated to activate DDR1 Pravastatin sodium rather than phosphorylation by TGF-β1 stimulation in MRC-5 lung fibroblasts. In summary, these results indicated EP300 as a potential therapeutic target of pulmonary fibrosis. In the present study, we further discovered the synergistic inhibitory potency of EP300 and DDR1 in vitro and in vivo. EP300 inhibition only partially suppressed the activation of fibrotic cytokines, inflammation cytokines, and COL1 A1 stimulated by TGF-β1 in vitro and bleomycin in vivo. The DDR1 inhibitor CQ-061 displayed improved therapeutic effects than EP300 inhibition individually; however, significant synergistic effects were observed in DDR1 and EP300 inhibition. According to these results, we speculated that these synergistic effects may come from the DDR1 transcription activator capacity of EP300. Therefore, the synergistic effect of DDR1 and EP300 inhibition on pulmonary fibrosis was determined in vivo by using bleomycin-induced pulmonary murine models. Our results suggested that the inhibition of DDR1 or EP300 resulted in reduced fibrotic and inflammation cytokines and alleviated pulmonary fibrosis in vivo. In consideration of the complex functions of EP300 in different diseases, further studies are necessary to develop in-depth insights into the mechanisms of EP300 in pulmonary fibrosis. In any case, our bioinformatics and experimental results suggested that close links between EP300 and DDR1 may serve as therapeutic target pair in suppressing TGF-β1 signaling in pulmonary fibroblasts and bleomycin-induced murine models.