AIM:To identify the effect of gefitinib on the expression of forkhead box protein O 3a (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 ), bleomy-cin group (received bleomycin intratracheally , 3 mg/kg), and bleomycin plus gefitinib group (received bleomycin intratra-cheally 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 fi-brosis 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 signifi-cantly.Meanwhile, phosphorylated EGFR and Akt were decreased .The level of α-SMA was observably increased .CON-CLUSION:Gefitinib restores Foxo3a activity and reduces α-SMA expression by modulating EGFR/Akt activity, thus in-hibiting bleomycin-induced lung fibrosis.%目的：研究吉非替尼对肺纤维化小鼠转录因子叉头框蛋白O3a（Foxo3a）活性、α-平滑肌肌动蛋白（α-SMA）水平及相关通路的影响，探讨吉非替尼抑制肺上皮-间质转分化的可能机制。方法：将30只SPF级雌性昆明小鼠随机分为3组：对照组（生理盐水气管内雾化）、博来霉素组（博来霉素3 mg/kg溶于100μL生理盐水气管内雾化）和吉非替尼处理组（博来霉素气管内雾化后，每天吉非替尼20 mg/kg溶于100μL生理盐水灌胃）。实验第14天收集样本，将小鼠肺组织置于10％中性甲醛固定，石蜡包埋切片后行HE与Masson染色；RT-PCR法检测Foxo3a和α-SMA mRNA表达水平；Western blotting 法检测表皮生长因子受体（EGFR）、Akt、Foxo3a和α-SMA蛋白表达水平。结果：吉非替尼处理组小鼠肺组织病理损伤较博来霉素组明显减轻，胶原沉积明显减少，炎症损伤评分及纤维化评分明显下降（均P＜0．01），Foxo3a mRNA表达水平明显升高（P＜0．05），α-SMA mRNA表达水平明显下降（P＜0．05），总Foxo3a蛋白表达增加，但Foxo3a磷酸化水平显著下降（P＜0．01），胞核Foxo3a蛋白明显增加（P＜0．05）；同时，EGFR和Akt磷酸化水平也显著下降（P＜0．01，P＜0．05），上皮-间质转分化标志蛋白α-SMA表达水平明显降低（P＜0．05）。结论：吉非替尼抑制博来霉素诱导的肺纤维化，其机制可能与抑制EGFR/Akt通路活化、增强转录因子Foxo3a活性、从而抑制上皮-间质转分化密切相关。
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