中国呼吸与危重监护杂志

中国呼吸与危重监护杂志

两种表皮生长因子抑制剂下调肿瘤抑制素 M 抑制博来霉素诱导的小鼠肺纤维化

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目的比较两种表皮生长因子酪氨酸激酶抑制剂(EGFR-TKI)吉非替尼和厄罗替尼对肿瘤抑制素 M(OSM)及下游通路的调节作用,以及对博来霉素诱导小鼠肺纤维化的干预作用。方法将 40 只 SPF 级雌性昆明小鼠随机分为对照组(生理盐水气管内雾化)、博来霉素组(博来霉素 3 mg/kg 气管内雾化)、吉非替尼组(博来霉素 3 mg/kg 气管内雾化后吉非替尼 20 mg·kg–1·d–1 灌胃)以及厄罗替尼组(博来霉素 3 mg/kg 气管内雾化后厄罗替尼 25 mg·kg–1·d–1 灌胃)。实验第 14 d 使用小动物 CT 对小鼠进行胸部 CT 检查,检查完毕后收集小鼠肺组织,行 HE、Masson 染色,Western blot 法检测肺组织 α 平滑肌肌动蛋白(α-SMA)、OSM、JAK1、p-JAK1、STAT3、p-STAT3 蛋白表达水平。结果吉非替尼和厄罗替尼处理后,小鼠胸部 CT 影像中肺部渗出及纤维化病灶较博来霉素组明显减少,肺组织病理损伤及纤维化损伤均较博来霉素组明显减轻(均 P<0.05),α-SMA 蛋白、OSM 蛋白、p-JAK1/JAK1、p-STAT3/STAT3 表达较博来霉素组明显下调(均P<0.05)。吉非替尼和厄罗替尼的上述作用无显著差异(均P>0.05)。结论两种表皮生长因子酪氨酸激酶抑制剂吉非替尼和厄罗替尼均能抑制博来霉素诱导的小鼠肺纤维化,其抑制作用相近,机制可能与下调 OSM 蛋白的表达以及下游 JAK/STAT 通路的磷酸化密切相关。

ObjectiveTo study effects of two kinds of epidermal growth factor receptor kinase inhibitors on bleomycin-induced pulmonary fibrosis in mice, and regulation mechanism on oncostatin M (OSM) and downstream signaling pathways.MethodsForty Kunming female mice were randomly divided into a control group, a fibrosis group, a gefitinib group, and an erlotinib group. The mice in the control group were administered with saline aerosol intratracheally. The mice in the fibrosis group were administered with bleomycin at a dose of 3 mg/kg aerosol intratracheally. The mice in the gefitinib group and the erlotinib group were administered with bleomycin at a dose of 3 mg/kg aerosol intratracheally and then gastrically perfused with gefitinib (20 mg·kg–1·d–1) or erlotinib (25 mg·kg–1·d–1). All mice accepted computer tomography examination 14 days after the treatment and then were sacrificed, and the lungs were collected for further detection. The lungs were stained with hematoxylin eosin and Masson’s trichrome, examined with Western blot for pathological examination and expressions of α-smooth muscle actin (α-SMA), OSM, Janus kinase 1 (JAK1), phospho-JAK1 (p-JAK1), signal transducers and activators of transcription 3 (STAT3), and phospho-STAT3 (p-STAT3) proteins.ResultsThe pathological injury of the lung in the gefitinib group and the erlotinib group was significantly relieved compared with that in the bleomycin group. The expressions of α-SMA, OSM, p-JAK1/JAK1, and p-STAT3/STAT3 proteins were also significantly reduced. There were no differences between the above-mentioned indexes between the gefitinib group and the erlotinib group.ConclusionsGefitinib and erlotinib can significantly relieve bleomycin-induced pulmonary fibrosis in mice. The underlying mechanism may be involved in inhibiting expression of OSM and downstream JAK/STAT pathways.

关键词: 肺纤维化; 表皮生长因子酪氨酸激酶抑制剂; 吉非替尼; 厄罗替尼; 肿瘤抑制素 M

Key words: Pulmonary fibrosis; Epidermal growth factor receptor kinase inhibitors; Gefitinib; Erlotinib; Oncostatin M

引用本文: 郑林鑫, 陈灿, 麦玉梅, 李理, 李伟峰. 两种表皮生长因子抑制剂下调肿瘤抑制素 M 抑制博来霉素诱导的小鼠肺纤维化. 中国呼吸与危重监护杂志, 2018, 17(4): 400-406. doi: 10.7507/1671-6205.201712029 复制

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