中和白介素⁃17对博来霉素诱导的特发性肺纤维化及PI3K/Akt/mTOR信号通路的影响
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河北省高等学校自然科学重点项目(ZD2017206)


Effects of neutralizing interleukin⁃17 on idiopathic pulmonary fibrosis induced by bleomycin and regulation of PI3K/Akt/mTOR signal pathway in mice
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    摘要:

    目的:研究中和白介素-17(interleukin-17,IL-17)对博来霉素(bleomycin,BLM)诱导特发性肺纤维化及PI3K/Akt/mTOR信号通路的影响。方法:C57BL/6小鼠随机分为对照组、BLM组、中和抗体组和自噬抑制组。BLM组、中和抗体组和自噬抑制组利用BLM(5 U/kg)诱导特发性肺纤维化模型形成,对照组给予等量生理盐水。造模第1天起自噬抑制组小鼠腹腔注射3-甲基腺嘌呤(3-methyladenine,3-MA),每周5次,连用4周,其他3组则注射等量的生理盐水。中和抗体组和自噬抑制组小鼠分别从造模后第3 d起,每隔3 d尾静脉注射抗鼠IL-17抗体,于28 d取材,采用Masson三色染色和羟脯氨酸(hydroxyproline,HYP)含量测定评价肺纤维化程度和胶原蛋白的表达变化,利用ELISA检测肺泡灌洗液中转化生长因子-β1(transform growth factor-β1,TGF-β1)的含量,Western blot分析LC3Ⅱ/LC3Ⅰ、Beclin-1、p62、p-PI3K/PI3K、p-Akt/Akt和p-mTOR/mTOR的蛋白表达。结果:与BLM组相比,中和抗体组羟脯氨酸和TGF-β1含量显著下降(P < 0.01),肺纤维化程度明显降低(P < 0.01),LC3Ⅱ/LC3Ⅰ比值和Beclin-1表达明显上调(P < 0.01,P < 0.05),p62表达减少(P < 0.05),而p-PI3K/PI3K、p-Akt/Akt、p-mTOR/mTOR比值显著降低(P < 0.05)。结论:IL-17在肺纤维化中的作用与抑制细胞自噬有关。中和内源性IL-17,能显著改善BLM诱导的肺纤维化,降低TGF-β1产生,抑制PI3K/Akt/mTOR信号通路,激活细胞自噬。

    Abstract:

    Objective:This study aims to observe the effects of neutralizing interleukin-17(IL-17)on bleomycin(BLM) induced idiopathic pulmonary fibrosis and PI3K/Akt/mTOR signaling pathway. Methods:C57BL/6 mice were randomly divided into control group,BLM group,neutralizing antibody group and autophagy inhibition group,respectively. BLM group,neutralizing antibody group and autophagy inhibition group were administrated BLM(5 U/kg) through a single intratracheal injection to induce idiopathic pulmonary fibrosis,while the control group was received the equivalent sterile saline. Meanwhile,autophagy inhibition group was injected 3-methyl adenine(3-MA) via intraperitoneal injection 5 times a week for 4 weeks. Other groups were given the same amount of sterile saline. Neutralizing antibody group and autophagy inhibition group were administrated neutralizing IL-17 mAb via caudal vein every 3 days from day 3 after model made. All mice were sacrificed after 28 days. Lung tissues were used to evaluate pulmonary fibrosis by Masson staining and collagen expression changes by hydroxyproline contents measurement. Bronchoalveolar lavage fluid was collected for transform growth factor-β1(TGF-β1) measurement by ELISA. The expression of LC3Ⅱ/LC3Ⅰ,Beclin-1,p62,p-PI3K/PI3K,p-Akt/Akt and p-mTOR/mTOR proteins were all assayed by Western blot. Results:Compared with BLM group,hydroxyproline content,TGF-β1 concentration and pulmonary fibrosis in neutralizing antibody group were significantly decreased(P < 0.01),the ratio of LC3Ⅱ/LC3Ⅰ and Beclin 1 expression significantly raised(P < 0.01,P < 0.05),p62 expression reduced remarkably(P < 0.05),and the ratio of p-PI3K/PI3K,p-Akt/Akt and p-mTOR/mTOR decreased significantly(P < 0.05). Conclusion:The mechanism of IL-17 in pulmonary fibrosis is related to inhibition of autophagy. Neutralization of endogenous IL-17 can significantly attenuate BLM-induced pulmonary fibrosis,reduce the production of TGF-β1,inhibit the PI3K/Akt/mTOR signaling pathway,and activate cell autophagy.

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宋桂芹,赵铁军,唐红悦,贺佳琪,邢晨浩,徐志伟,程建贞,张效云.中和白介素⁃17对博来霉素诱导的特发性肺纤维化及PI3K/Akt/mTOR信号通路的影响[J].南京医科大学学报(自然科学版),2020,(11):1617-1622

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  • 收稿日期:2019-12-20
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  • 在线发布日期: 2020-12-04
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