Journalartikel

Jahr der Veröffentlichung: 2018

Seiten: 276-293

Zeitschrift: EMBO Molecular Medicine

Bandnummer: 10

Heftnummer: 2

ISSN: 1757-4676

eISSN: 1757-4684

Open Access Status: Gold

DOI Link: https://doi.org/10.15252/emmm.201606261

Verlag: Springer

Abstract: 
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal parenchymal lung disease with limited therapeutic options, with fibroblast-to-myofibroblast transdifferentiation and hyperproliferation playing a major role. Investigating exvivo-cultured (myo)fibroblasts from human IPF lungs as well as fibroblasts isolated from bleomycin-challenged mice, Forkhead box O3 (FoxO3) transcription factor was found to be less expressed, hyperphosphorylated, and nuclear-excluded relative to non-diseased controls. Downregulation and/or hyperphosphorylation of FoxO3 was reproduced by exposure of normal human lung fibroblasts to various pro-fibrotic growth factors and cytokines (FCS, PDGF, IGF1, TGF-1). Moreover, selective knockdown of FoxO3 in the normal human lung fibroblasts reproduced the transdifferentiation and hyperproliferation phenotype. Importantly, mice with global- (Foxo3(-/-)) orfibroblast-specific (Foxo3(f.b)(-/-)) FoxO3 knockout displayed enhanced susceptibility to bleomycin challenge, with augmented fibrosis, loss of lung function, and increased mortality. Activation of FoxO3 with UCN-01, a staurosporine derivative currently investigated in clinical cancer trials, reverted the IPF myofibroblast phenotype invitro and blocked the bleomycin-induced lung fibrosis invivo. These studies implicate FoxO3 as a critical integrator of pro-fibrotic signaling in lung fibrosis and pharmacological reconstitution of FoxO3 as a novel treatment strategy.

Harvard-Zitierstil: Al-Tamari, H., Dabral, S., Schmall, A., Sarvari, P., Ruppert, C., Paik, J., et al. (2018) FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis, EMBO Molecular Medicine, 10(2), pp. 276-293. https://doi.org/10.15252/emmm.201606261

APA-Zitierstil: Al-Tamari, H., Dabral, S., Schmall, A., Sarvari, P., Ruppert, C., Paik, J., DePinho, R., Grimminger, F., Eickelberg, O., Guenther, A., Seeger, W., Savai, R., & Pullamsetti, S. (2018). FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis. EMBO Molecular Medicine. 10(2), 276-293. https://doi.org/10.15252/emmm.201606261