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- W4313133139 abstract "Myofibroblasts, considered main drivers in IPF, gather in fibrotic foci where adjacent macrophages secrete mediators affecting their function. Of special interest is PGE<sub>2</sub>, which acutely peaks during early inflammation and reemerges with extended high levels in the post-resolution phase. Here, we mimic the resolution milieu by chronic high dose PGE<sub>2</sub> to study transcriptomic, metabolic and phenotypic changes in IPF myofibroblasts and macrophages. TGF-β1-induced myofibroblasts were treated with 500 nM PGE<sub>2</sub> and global transcription was studied by RNA-Seq. High content imaging was used to confirm results in a myofibroblast reversal assay and fibroblast metabolic changes were studied by Seahorse analysis. PGE<sub>2</sub>-treated IPF BAL macrophages were analyzed by a fibrosis and resolution-focused QuantiGene RNA assay. PGE<sub>2</sub> reverted 156 of the 392 genes changed by TGF-β1 in fibroblasts, including genes encoding αSMA, Col I and PAI-1 and the phenotypic myofibroblast reversal assay showed a significant decrease of αSMA positive IPF myofibroblasts. Augmented glycolysis and increased fatty acid oxidation (FAO) was observed in TGF-β1-derived myofibroblasts. Both glycolysis and exogenous FAO rate was reduced upon prolonged PGE<sub>2</sub> treatment. PGE<sub>2</sub> also had a profound effect on macrophage phenotype with a reduction in key inflammatory and pro-fibrotic genes, while upregulating resolution-type markers. Our results show the importance of PGE<sub>2</sub> in driving an anti-fibrotic phenotypic switch in IPF and mechanistic knock-down studies of PGE<sub>2</sub>-inducible genes are ongoing to identify the key factors involved. Activation of this process may lead to new therapies targeting fibrotic disease." @default.
- W4313133139 created "2023-01-06" @default.
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- W4313133139 date "2022-09-04" @default.
- W4313133139 modified "2023-09-23" @default.
- W4313133139 title "A transcriptomic, metabolic and phenotypic study of the anti-fibrotic effects of PGE2 in IPF lung fibroblasts and macrophages" @default.
- W4313133139 doi "https://doi.org/10.1183/13993003.congress-2022.928" @default.
- W4313133139 hasPublicationYear "2022" @default.
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