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铁死亡参与油酸诱导的小鼠急性肺损伤

周航^1,2, 李凤^1,2, 牛建一^1,2, 钟伟勇^1,2, 汤敏誉^1,2, 林栋^1,2, 崔洪珲^1,2, 黄学涵^1,2, 陈莹莹^1,3, 王红艳⁴, 涂永生^1,*

¹广州医科大学基础医学院生理教研室，广州 511436；²广州医科大学第一临床学院，广州 511436；³广州医科大学第六临床学院，广州 511436；⁴广州医科大学基础医学院病理教研室，广州 511436

摘要

本研究旨在探讨铁死亡在油酸(oleic acid, OA)致急性肺损伤(acute lung injury, ALI)小鼠模型中的作用。小鼠尾静脉注射纯OA制备ALI模型，以肺组织病理学评分、肺湿干重比、支气管肺泡灌洗液(bronchoalveolar lavage fluid, BALF)蛋白含量作为ALI的评价指标，用试剂盒检测肺组织的铁浓度、谷胱甘肽(glutathione, GSH)和丙二醛(malondialdehyde, MDA)含量，用透射电子显微镜观察肺细胞的超微结构，用定量PCR (q-PCR)检测肺组织中前列腺素内过氧化物合酶2 (prostaglandin-endoperoxide synthase 2, PTGS2) mRNA表达，用Western blot测定肺组织谷胱甘肽过氧化物酶4 (glutathione peroxidase 4, GPX4)、铁蛋白和转铁蛋白受体1 (transferrin receptor 1, TfR1)的蛋白表达水平。结果表明，OA组小鼠肺组织病理评分、肺湿干重比和BALF中蛋白均高于对照组。OA组小鼠肺细胞线粒体缩小，线粒体膜破裂。与对照组相比，OA组PTGS2 mRNA表达增加7倍。OA组小鼠肺组织出现铁过载、GSH含量减少和MDA累积。与对照组相比，OA组小鼠肺组织GPX4和铁蛋白表达水平下调。以上结果提示，铁死亡可能在ALI发病机制中发挥作用，这为治疗ALI的新药开发提供了新的角度。

关键词： 铁死亡; 油酸; 急性肺损伤; 谷胱甘肽; 谷胱甘肽过氧化物酶4; 铁

分类号：R363

Ferroptosis was involved in the oleic acid-induced acute lung injury in mice

ZHOU Hang^1,2, LI Feng^1,2, NIU Jian-Yi^1,2, ZHONG Wei-Yong^1,2, TANG Min-Yu^1,2, LIN Dong^1,2, CUI Hong-Hui^1,2, HUANG Xue-Han^1,2, CHEN Ying-Ying^1,3, WANG Hong-Yan⁴, TU Yong-Sheng^1,*

¹Department of Physiology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China；²The First Clinical Medical College, Guangzhou Medical University, Guangzhou 511436, China；³The Sixth Clinical Medical College, Guangzhou Medical University, Guangzhou 511436, China；⁴Department of Pathology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China

Abstract

The aim of the present study was to investigate the role of ferroptosis in acute lung injury (ALI) mouse model induced by oleic acid (OA). ALI was induced in the mice via the lateral tail vein injection of pure OA. The histopathological score of lung, lung wet-dry weight ratio and the protein content of bronchoalveolar lavage fluid (BALF) were used as the evaluation indexes of ALI. Iron concentration, glutathione (GSH) and malondialdehyde (MDA) contents in the lung tissues were measured using corresponding assay kits. The ultrastructure of pulmonary cells was observed by transmission electron microscope (TEM), and the expression level of prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA was detected by quantitative polymerase chain reaction (q-PCR). Protein expression levels of glutathione peroxidase 4 (GPX4), ferritin and transferrin receptor 1 (TfR1) in lung tissues were determined by Western blot. The results showed  that histopathological scores of lung tissues, lung wet-dry weight ratio and protein in BALF in the OA group were higher than those of the control group. In the OA group, the mitochondria of pulmonary cells were shrunken, and the mitochondrial membrane was ruptured. The expression level of PTGS2 mRNA in the OA group was seven folds over that in the control group. Iron overload, GSH depletion and accumulation of MDA were observed in the OA group. Compared with the control group, the protein expression levels of GPX4 and ferritin in lung tissue were down-regulated in the OA group. These results suggest that ferroptosis plays a potential role in the pathogenesis of ALI in our mouse model, which may provide new insights for development of new drugs for ALI. 

Key words: acute lung injury; oleic acid; ferroptosis; glutathione; glutathione peroxidase 4; iron

收稿日期：2019-02-28　　录用日期：2019-07-01

通讯作者：涂永生　　E-mail: tuys@gzhmu.edu.cn

DOI: 10.13294/j.aps.2019.0070

引用本文：

周航, 李凤, 牛建一, 钟伟勇, 汤敏誉, 林栋, 崔洪珲, 黄学涵, 陈莹莹, 王红艳, 涂永生. 铁死亡参与油酸诱导的小鼠急性肺损伤[J]. 生理学报 2019; 71 (5): 689-697.

ZHOU Hang, LI Feng, NIU Jian-Yi, ZHONG Wei-Yong, TANG Min-Yu, LIN Dong, CUI Hong-Hui, HUANG Xue-Han, CHEN Ying-Ying, WANG Hong-Yan, TU Yong-Sheng. Ferroptosis was involved in the oleic acid-induced acute lung injury in mice. Acta Physiol Sin 2019; 71 (5): 689-697