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  • Chlorprothixene Pulmonary fibroblasts can regulate the

    2020-10-17

    Pulmonary fibroblasts can regulate the wound healing process by secreting and processing extracellular matrix (ECM), chemokines, and cytokines. However, persistent and atypical fibroblast proliferation can result in ECM accumulation and may trigger the onset or development of pulmonary fibrosis [[17], [18], [19]]. In these biochemical processes, transforming growth factor β1 (TGF-β1) is an important regulator of fibroblast differentiation in IPF [[20], [21], [22], [23], [24]]. Ghosh et al. reported that TGF-β1 up-regulated the mRNA and protein expression of EP300 in both skin and lung fibroblasts, and that the transcriptional activation and accumulation of EP300 mRNA in these Chlorprothixene was both time and dose-dependent [[25], [26], [27]]. Although the biological functions of EP300 in hematopoietic and epithelial cells have been extensively investigated, their effects in would healing processes of fibroblasts have not been fully explored. Some recent research indicates that TGF-β1 can stimulate EP300 in inflammation, fibrosis and cancer [28]. Beyond the typical transcriptional cofactor, EP300 can regulate target gene expression without directly binding to DNA by possessing intrinsic acetyltransferase activity. EP300 plays an important role in cell proliferation, differentiation, and apoptosis, as well as cellular epigenetic modification by acetylation of target protein and transcription factors [29,30]. Several studies indicate that the dysregulation of EP300 is involved in several diseases, such as inflammation, cardiac hypertrophy, fibrotic diseases [29]. Although the protein structure and biological function of EP300 has been extensively studied in cancer and epithelial cells, its role and molecular mechanisms in the TGF-β1 pathway are remain unclear. Discoidin domain receptor 1 (DDR1) is a transmembrane receptor belonging to the RTK (receptor tyrosine kinases) superfamily [31]. DDR1 is one of the main collagen receptors located in several cell types, and can regulate several cell functions after collagen binding, including cell adhesion, proliferation, ECM homeostasis and differentiation [[32], [33], [34]]. Within the intracellular kinase domain of DDR1, there exists multiple tyrosine residues that can recruit and phosphorylate substrate proteins, such as PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) and SHP-2 [35]. Moreover, DDR1 can regulate signaling pathways in a cell type specific manner. For example, DDR1 stimulates ERK signaling pathway in vascular smooth muscle cells but cannot significantly affect the ERK pathway in breast cancer cells and suppress ERK pathways in glomerular mesangial cells [36]. In addition, DDR1 can also process extracellular signals from cytokines and other ECM receptors. Recently, there have been several studies conducted to explore the individual function of DDR1 and EP300 in organ fibrosis, such as kidney fibrosis, pulmonary fibrosis, and skin fibrosis [31,33,34,37]. Using bleomycin induced models, we have discovered a series of novel DDR1 inhibitors that can prevent or ameliorate lung inflammation and fibrosis on. However, the relationship between DDR1 and EP300 expression, as well as their signaling pathways in pulmonary fibrosis, remains unexplored. Accordingly, we have focused on investigating the expression and molecular mechanisms of EP300/DDR1 in the context of pulmonary fibrosis. We showed that both EP300 and DDR1 expression were significantly increased in lung tissues from IPF patients. Both activation of EP300 by TGF-β1 and overexpression of EP300 activated lung fibroblasts through regulating the transcription of FN1 and DDR1. In addition, DDR1 and EP300 inhibitors synergistically exerted protective effects in bleomycin-induced pulmonary fibrosis models. Our results provided experimental evidence that combined EP300 and DDR1 therapy as promising therapeutic strategies for treating pulmonary fibrosis.
    Results
    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.