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Al-Tamari, Hamza M.; Dabral, Swati; Schmall, Anja; Sarvari, Pouya; Ruppert, Clemens; Paik, Jihye; DePinho, Ronald A.; Grimminger, Friedrich; Eickelberg, Oliver; Günther, Andreas; Seeger, Werner; Savai, Rajkumar; Pullamsetti, Soni S. (2018): FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis. In: EMBO Molecular Medicine, Vol. 10, No. 2: pp. 276-293
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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.