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 ex vivo-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-beta1). Moreover, selective knockdown of FoxO3 in the normal human lung fibroblasts reproduced the transdifferentiation and hyperproliferation phenotype. Importantly, mice with global- (Foxo3(-/-)) or fibroblast-specific (Foxo3f.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 in vitro and blocked the bleomycin-induced lung fibrosis in vivo 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.
- Al-Tamari, H. M.
- Dabral, S.
- Schmall, A.
- Sarvari, P.
- Ruppert, C.
- Paik, J.
- DePinho, R. A.
- Grimminger, F.
- Eickelberg, O.
- Guenther, A.
- Seeger, W.
- Savai, R.
- Pullamsetti, S. S.
Keywords
- fibroblast
- forkhead box O transcription factors
- idiopathic pulmonary fibrosis
- myofibroblast
- transdifferentiation
