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Marchal-Duval, Emmeline; Homps-Legrand, Méline; Froidure, Antoine; Jaillet, Madeleine; Ghanem, Mada; Lou, Deneuville; Justet, Aurélien; Maurac, Arnaud; Vadel, Aurelie; Fortas, Emilie; Cazes, Aurelie; Joannes, Audrey; Giersh, Laura; Mal, Herve; Mordant, Pierre; Piolot, Tristan; Truchin, Marin; Mounier, Carine M; Schirduan, Ksenija; Korfei, Martina; Gunther, Andreas; Mari, Bernard; Jaschinski, Frank; Crestani, Bruno;

Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis

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  • Medientyp: E-Artikel
  • Titel: Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis
  • Beteiligte: Marchal-Duval, Emmeline; Homps-Legrand, Méline; Froidure, Antoine; Jaillet, Madeleine; Ghanem, Mada; Lou, Deneuville; Justet, Aurélien; Maurac, Arnaud; Vadel, Aurelie; Fortas, Emilie; Cazes, Aurelie; Joannes, Audrey; Giersh, Laura; Mal, Herve; Mordant, Pierre; Piolot, Tristan; Truchin, Marin; Mounier, Carine M; Schirduan, Ksenija; Korfei, Martina; Gunther, Andreas; Mari, Bernard; Jaschinski, Frank; Crestani, Bruno;
  • Erschienen: eLife Sciences Publications, Ltd, 2023
  • Erschienen in: eLife
  • Sprache: Englisch
  • DOI: 10.7554/elife.79840
  • ISSN: 2050-084X
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p>Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix remodeling could be a promising avenue for IPF treatment. Analysis of transcriptomic database identified the mesenchymal transcription factor PRRX1 as upregulated in IPF. PRRX1, strongly expressed by lung fibroblasts, was regulated by a TGF-β/PGE2 balance in vitro in control and IPF human lung fibroblasts, while IPF fibroblast-derived matrix increased <jats:italic>PRRX1</jats:italic> expression in a PDGFR-dependent manner in control ones. PRRX1 inhibition decreased human lung fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-β driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to TGF-β response global decrease. Finally, targeted inhibition of <jats:italic>Prrx1</jats:italic> attenuated fibrotic remodeling in vivo with intra-tracheal antisense oligonucleotides in bleomycin mouse model of lung fibrosis and ex vivo using human and mouse precision-cut lung slices. Our results identified PRRX1 as a key mesenchymal transcription factor during lung fibrogenesis.</jats:p>
  • Zugangsstatus: Freier Zugang