Gefitinib inhibits epithelial-mesenchymal transition by up-regulating Foxo3a expression in mice with bleomycin-induced lung fibrosis

AIM：To identify the effect of gefitinib on the expression of forkhead box protein O3a (Foxo3a), α-smooth muscle actin (α-SMA) and related signal pathway molecules in the mice with bleomycin-induced lung fibrosis and to investigate the inhibition mechanism of gefitinib on lung epithelial-mesenchymal transition. METHODS：Thirty Kunming female mice were randomly divided into 3 groups:control group (received normal saline intratracheally), bleomycin group (received bleomycin intratracheally, 3 mg/kg), and bleomycin plus gefitinib group (received bleomycin intratracheally and gefitinib orally, 20 mg/kg). All the mice were sacrificed 14 d after the treatments. Pulmonary histological changes were evaluated by hematoxylin-eosin staining and Masson trichrome staining. The mRNA levels of Foxo3a and α-SMA in the lung tissues were detected by RT-PCR. Nuclear Foxo3a, α-SMA, and phosphorylation of EGFR, Akt and Foxo3a in the lung tissues were determined by Western blotting. RESULTS：Gefitinib inhibited bleomycin-induced lung fibrosis and significantly decreased the scores of lung inflammation and fibrosis. Foxo3a mRNA expression and total Foxo3a protein expression were increased, while the phosphorylated Foxo3a was decreased. Nuclear Foxo3a was increased significantly. Meanwhile, phosphorylated EGFR and Akt were decreased. The level of α-SMA was observably increased. CONCLUSION:Gefitinib restores Foxo3a activity and reduces α-SMA expression by modulating EGFR/Akt activity, thus inhibiting bleomycin-induced lung fibrosis.