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Cell Biol Int. 2018 Sep;42(10):1311-1320. doi: 10.1002/cbin.11016. Epub 2018 Jul 2.

Lipopolysaccharide induced the proliferation of mouse lung fibroblasts by suppressing FoxO3a/p27 pathway.

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Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.


Aberrant aggregation and activation of lung fibroblasts is a key process in pulmonary fibrosis, but the underlying mechanism remains enigmatic. Forkhead Box O3a (FoxO3a) is considered to be an important transcription factor that could regulate both cell cycle and cell viability. To investigate the role of FoxO3a on LPS-induced lung fibroblast proliferation, we transfected FoxO3a-SiRNA or FoxO3a-OE lentivirus into cultured mouse lung fibroblasts to knockdown or overexpress FoxO3a and pretreated mouse lung fibroblasts with gefitinib to enhance FoxO3a activity. The proliferation of lung fibroblasts was evaluated by CCK8 assay, the expression of FoxO3a, phosphorylated FoxO3a (p-FoxO3a) and p27 were measured by Western blot. We found that the proliferation of mouse lung fibroblasts mediated by LPS is accompanied by the inactivation of FoxO3a. The knockdown of FoxO3a could further decreased the expression of p27 mediated by LPS, while the overexpression of FoxO3a significantly increased the expression of p27 and suppressed LPS-induced lung fibroblast proliferation. Upon treating fibroblasts with gefitinib, the phosphorylation of FoxO3a was reduced and FoxO3a translocated into the nucleus, the expression of p27 was significantly increased and the proliferation of lung fibroblasts mediated by LPS could also be inhibited effectively. The results indicate that overexpression and reduced phosphatase activity of FoxO3a inhibit LPS-induced lung fibroblast proliferation through the activation of FoxO3a/p27 signaling pathways. Thus, to enhance FoxO3a activity could be a potential therapeutic target for LPS-induced pulmonary fibrosis.


FoxO3a; gefitinib; lipopolysaccharide; pulmonary fibrosis

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