ORMDL3 通过内质网应激介导的细胞自噬在中性粒细胞哮喘中的作用机制研究
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山东中医药高等专科学校,西医教学部,山东 烟台 264199

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R-33

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Role and mechanism of ORMDL3 in neutrophil asthma through endoplasmic reticulum stress-mediated autophagy
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Western Medicine Teaching Department, Shandong College of Traditional Chinese Medicine, Yantai 264199, China

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    摘要:

    目的 研究 ORMDL3 通过内质网应激(ERS)介导的细胞自噬在中性粒细胞哮喘中的作用机制。 方法 成年雄性 SD 大鼠随机分为对照组、模型组、模型+NC-siRNA 组、模型+ORMDL3-siRNA 组、溶剂对照组、模型+ 溶剂组、模型+NC-siRNA+溶剂组、模型+ORMDL3-siRNA+溶剂组、模型+ORMDL3-siRNA+激动剂组,采用脂多糖+卵白蛋白联合致敏的方式建立中性粒细胞哮喘模型,经气道注射 ORMDL3-siRNA 慢病毒或阴性对照(NC)-siRNA 慢病毒,腹腔注射 ERS 激动剂毒胡萝卜素或溶剂。 检测气道功能 0. 2 s 用力呼气容积(FEV0. 2) / 用力肺活量(FVC) 以及呼气峰流速(PEF),肺组织病理改变,ORMDL3、ERS 标志基因 PERK、IRE1α、ATF6 及自噬标志基因 Beclin-1、 LC3 的表达水平。 结果 模型组大鼠的 FEV0. 2 / FVC、PEF 水平低于对照组,肺组织中 ORMDL3、PERK、IRE1α、 ATF6、Beclin-1、LC3-II/ LC3-I 的表达水平高于对照组(P<0. 05);模型+ORMDL3-siRNA 组大鼠的 FEV0. 2 / FVC、PEF 水平高于模型+NC-siRNA 组,肺组织中 ORMDL3、ATF6、Beclin-1、LC3-II/ LC3-I 的表达水平低于模型+NC-siRNA 组 (P<0. 05)。 PERK、IRE1α 的表达水平与模型+NC-siRNA 组比较无差异(P>0. 05);模型+ORMDL3-siRNA+激动剂组大鼠的 FEV0. 2 / FVC、PEF 水平低于模型+ORMDL3-siRNA+溶剂组,肺组织中 Beclin-1、LC3-II/ LC3-I 的表达水平高于模型+ORMDL3-siRNA+溶剂组(P<0.05)。 结论 在中性粒细胞哮喘的发病中,ORMDL3 通过 ERS 的 ATF6 通路激活细胞自噬是可能的分子机制,阻断 ORMDL3 是治疗中性粒细胞哮喘的可能靶点。

    Abstract:

    Objective To investigate the role and mechanism of ORMDL3 in neutrophil asthma through endoplasmic reticulum stress ( ERS)-mediated autophagy. Methods Adult male SD rats were randomly divided into control, model, model+NC siRNA, model+ORMDL3 siRNA, solvent control, model+solvent control, model+NC siRNA group+ solvent control, model + ORMDL3 siRNA + solvent control and model + ORMDL3 siRNA + agonist groups. The neutrophil asthma model was established by lipopolysaccharide and ovalbumin sensitization. An ORMDL3 siRNA lentivirus or negative control (NC)-siRNA lentivirus was administered through the airway and ERS agonist, carotene, or solvent was injected intraperitoneally. Airway function, 0. 2 s forced expiratory volume (FEV0. 2) / forced vital capacity (FVC), peak expiratory flow ( PEF), pathological changes of lung tissue and the expression levels of ORMDL3, ERS marker genes PERK, IRE1α, ATF6 and autophagy marker genes Beclin-1 and LC3 were analyzed. Results FEV0. 2 / FVC and PEF levels of the model group were lower than those of the control group and the expression levels of ORMDL3, PERK, IRE1α, ATF6, Beclin-1 and LC3-II/ LC3-I in lung tissue were higher than those of the control group (P<0.05). FEV0. 2 / FVC and PEF levels of the model+ORMDL3-siRNA group were higher than those of the model+NC-siRNA group and the expression levels of ORMDL3, ATF6, Beclin-1 and LC3-II/ LC3-I in lung tissue were lower than those of the model+NC-siRNA group (P<0. 05). The expression levels of PERK and IRE1α showed no difference compared with the model+NC-siRNA group (P> 0.05). FEV0. 2 / FVC and PEF levels in the model+ORMDL3 siRNA+agonist group were lower than those in the model +ORMDL3 siRNA+solvent group and the expression levels of Beclin-1 and LC3-II/ LC3-I in lung tissue were higher than those in the control group ( P< 0.05 ). Conclusions In the pathogenesis of neutrophil asthma, ORMDL3-induced autophagy through ERS ATF6 pathway is a possible molecular mechanism. Blocking ORMDL3 is a possible treatment method for neutrophil asthma.

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王龙梅,孙永显,张新鹃,陈晓艳. ORMDL3 通过内质网应激介导的细胞自噬在中性粒细胞哮喘中的作用机制研究[J].中国比较医学杂志,2022,32(3):46~53.

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  • 收稿日期:2021-01-18
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  • 在线发布日期: 2022-04-18
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