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外源性给予氯化锌改善大鼠肺缺血/再灌注损伤

王淑远¹, 徐俊鹏², 程缘², 黄曼², 陈思安², 李卓伦², 张淇昊², 戴雍月², 尤利益³, 王万铁^2,*

¹温州市人民医院呼吸内科，温州 325400；²温州医科大学缺血/再灌注损伤研究所，温州 325035；³温州市人民医院超声科，温州 325400

摘要

本研究旨在探讨肺组织Zn2+在大鼠肺缺血/再灌注(ischemia/reperfusion, I/R)损伤发病机制中的作用。将雄性SpragueDawley (SD)大鼠随机分为对照组、肺I/R组(I/R组)、肺I/R+低剂量氯化锌组(LZnCl2+I/R组)、肺I/R+高剂量氯化锌组(HZnCl2+I/R组)、肺I/R+中剂量氯化锌组(MZnCl2+I/R组)以及TPEN+MZnCl2+I/R组(每组8只)。采用电感耦合等离子体质谱(ICP-MS)检测肺组织Zn2+浓度，通过观察HE染色、肺泡损伤指数、肺湿干重比及肺组织大体变化分析各组肺组织损伤程度，用TUNEL染色检测肺组织细胞凋亡，用Western blot和RT-qPCR检测肺组织caspase-3、ZIP8蛋白表达及锌转运蛋白(ZIP、ZNT) mRNA表达水平；用JC-1线粒体膜电位检测试剂盒测定肺组织线粒体膜电位。结果显示，与对照组相比，I/R组肺组织明显受损，肺湿干重比及肺泡损伤指数显著升高，肺组织Zn2+浓度显著下降，cleaved caspase-3/caspase-3比值及凋亡水平显著升高，ZIP8 mRNA和蛋白表达水平显著下调，其他锌转运蛋白mRNA表达水平无明显变化，线粒体膜电位显著降低；与I/R组相比，MZnCl2+I/R组和HZnCl2+I/R组肺组织损伤明显减轻，肺湿干重比及肺泡损伤指数显著降低，肺组织Zn2+浓度明显升高，cleaved caspase-3/caspase-3比值及凋亡水平显著下降，ZIP8 mRNA和蛋白表达明显上调，线粒体膜电位显著升高；Zn2+螯合剂TPEN可逆转中剂量ZnCl2对I/R组肺组织的上述保护作用。上述结果提示，外源性给予ZnCl2可以改善大鼠肺I/R损伤。

关键词： 锌离子; 肺缺血/再灌注损伤; 凋亡; 线粒体膜电位

Exogenous administration of zinc chloride improves lung ischemia/reperfusion injury in rats

WANG Shu-Yuan¹, XU Jun-Peng², CHENG Yuan², HUANG Man², CHEN Si-An², LI Zhuo-Lun², ZHANG Qi-Hao², DAI Yong-Yue², YOU Li-Yi³, WANG Wan-Tie^2,*

¹Department of Respiratory Medicine, Wenzhou People's Hospital, Wenzhou 325400, China；²Institute of Ischemia/Reperfusion Injury, Wenzhou Medical University, Wenzhou 325035, China；³Department of Ultrasound, Wenzhou People's Hospital, Wenzhou 325400, China

Abstract

The aim of this study was to investigate the contribution of lung zinc ions to pathogenesis of lung ischemia/reperfusion (I/ R) injury in rats. Male Sprague Dawley (SD) rats were randomly divided into control group, lung I/R group (I/R group), lung I/R + low-dose zinc chloride group (LZnCl2+I/R group), lung I/R + high-dose ZnCl2 group (HZnCl2+I/R group), lung I/R + medium-dose ZnCl2 group (MZnCl2+I/R group) and TPEN+MZnCl2+I/R group (n = 8 in each group). Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure the concentration of zinc ions in lung tissue. The degree of lung tissue injury was analyzed by observing HE staining, alveolar damage index, lung wet/dry weight ratio and lung tissue gross changes. TUNEL staining was used to detect cellular apoptosis in lung tissue. Western blot and RT-qPCR were used to determine the protein expression levels of caspase-3 and ZIP8, as well as the mRNA expression levels of zinc transporters (ZIP, ZNT) in lung tissue. The mitochondrial membrane potential (MMP) of lung tissue was detected by JC-1 MMP detection kit. The results showed that, compared with the control group, the lung tissue damage, lung wet/dry weight ratio and alveolar damage index were significantly increased in the I/R group. And in the lung tissue, the concentration of Zn2+ was markedly decreased, while the cleaved caspase-3/caspase-3 ratio and apoptotic levels were significantly increased. The expression levels of ZIP8 mRNA and protein were down-regulated significantly, while the mRNA expression of other zinc transporters remained unchanged. There was also a significant decrease in MMP. Compared with the I/R group, both MZnCl2+I/R group and HZnCl2+I/R group exhibited significantly reduced lung tissue injury, lung wet/dry weight ratio and alveolar damage index, increased Zn2+ concentration, decreased ratio of cleaved caspase-3/caspase-3 and apoptosis, and up-regulated expression levels of ZIP8 mRNA and protein. In addition, the MMP was significantly increased in the lung tissue. Zn2+ chelating agent TPEN reversed the above-mentioned protective effects of medium-dose ZnCl2 on the lung tissue in the I/R group. The aforementioned results suggest that exogenous administration of ZnCl2 can improve lung I/R injury in rats.

Key words: zinc ion; lung ischemia/reperfusion injury; apoptosis; mitochondrial membrane potential

收稿日期：　　录用日期：

通讯作者：王万铁　　E-mail:

DOI: 10.13294/j.aps.2025.0038

引用本文：

王淑远, 徐俊鹏, 程缘, 黄曼, 陈思安, 李卓伦, 张淇昊, 戴雍月, 尤利益, 王万铁. 外源性给予氯化锌改善大鼠肺缺血/再灌注损伤[J]. 生理学报 2025; 77 (5): 811-819.

WANG Shu-Yuan, XU Jun-Peng, CHENG Yuan, HUANG Man, CHEN Si-An, LI Zhuo-Lun, ZHANG Qi-Hao, DAI Yong-Yue, YOU Li-Yi, WANG Wan-Tie. Exogenous administration of zinc chloride improves lung ischemia/reperfusion injury in rats. Acta Physiol Sin 2025; 77 (5): 811-819 (in Chinese with English abstract).