[骨髓间充质干细胞提取的外泌体通过 miR-335 调控 NF-κB 通路并减轻大鼠肺缺血再灌注损伤]

Q3 Medicine
生理学报 Pub Date : 2024-04-25
Bing Zhang, Chao Meng, Ji-Yu Kang, Hua-Cheng Zhou
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引用次数: 0

摘要

本研究旨在探讨骨髓间充质干细胞外泌体(BMSCs-EXO)对大鼠肺缺血再灌注损伤(IRI)的影响以及miR-335的作用。大鼠肺缺血再灌注损伤模型是通过剪开左肺肺门60分钟并开放180分钟而建立的。40只Sprague-Dawley大鼠被随机分为假组、IRI组、IRI+PBS组、IRI+EXO组和IRI+miR-335抑制剂EXO(IRI+inhibitor-EXO)组(n = 8)。假组大鼠在不进行 IRI 的情况下进行开胸手术。IRI组大鼠用于建立IRI模型,无任何额外治疗。IRI+PBS组、IRI+EXO组和IRI+抑制剂-EXO组的大鼠用于建立IRI模型,并在再灌注前分别给予PBS、未做任何处理的来自BMSCs的EXO和含有miR-335抑制剂的来自BMSCs的EXO。实验期间对血气进行分析。再灌注结束时测量肺组织干湿比(W/D)、白细胞介素 1β(IL-1β)、肿瘤坏死因子α(TNF-α)、髓过氧化物酶(MPO)、丙二醛(MDA)和超氧化物歧化酶(SOD)。用电子显微镜观察线粒体,并计算弗拉明评分。用光学显微镜观察肺组织病理学和细胞凋亡(TUNEL 染色),并检测肺损伤评分(LIS)和细胞凋亡指数(AI)。用 RT-qPCR 检测 miR-335 的表达,用 Western blot 检测再灌注结束时 caspase-3、裂解-caspase-3、caspase-9、裂解-caspase-9 和 NF-κB 蛋白的表达。结果显示,与假组相比较,IRI组和IRI+PBS组再灌注后的氧合指数、pH值和碱过量(BE)明显降低,而IRI+EXO组的这些指数明显高于IRI+PBS组(P<0.05)。与假体组相比,IRI 组的 W/D、IL-1β、TNF-α、MPO、MDA、LIS、AI、Flameng 评分、caspase-3、裂解-caspase-3、caspase-9 和裂解-caspase-9 均明显升高,而 SOD、miR-335 和 NF-κB 则明显降低(P < 0.05)。这些指标在 IRI 组和 IRI+PBS 组中没有明显差异。与 IRI+PBS 组相比,IRI+EXO 组的 W/D、IL-1β、TNF-α、MPO、MDA、LIS、AI、Flameng 评分、caspase-3、裂解-caspase-3、caspase-9 和裂解-caspase-9 显著下降,但 SOD、miR-335 和 NF-κB 显著增加(P < 0.05)。与 IRI+EXO 组相比,IRI+抑制剂-EXO 组上述指标的变化有所逆转,但仍优于 IRI+PBS 组(P < 0.05)。结果表明,BMSCs-EXO 可通过上调 miR-335 减轻大鼠肺 IRI,激活 NF-κB 通路,维持线粒体稳定性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
[Exosomes derived from bone marrow mesenchymal stem cells regulate NF-κB pathway and reduce lung ischemia-reperfusion injury in rats by miR-335].

This study aimed to investigate the effect of exosomes derived from bone marrow mesenchymal stem cells (BMSCs-EXO) on lung ischemia-reperfusion injury (IRI) in rats and to explore the role of miR-335. The model of rat lung IRI was established by clipping the hilum of left lung for 60 min and opening for 180 min. Forty Sprague-Dawley rats were randomly divided into sham group, IRI group, IRI+PBS group, IRI+EXO group, and IRI+miR-335 inhibitor EXO (IRI+inhibitor-EXO) group (n = 8). Rats in the sham group underwent thoracotomies without IRI. Rats in the IRI group were used to establish IRI model without any additional treatment. In the IRI+PBS, IRI+EXO, and IRI+inhibitor-EXO groups, the rats were used to establish IRI model and given PBS, EXO from BMSCs without any treatment, and EXO from BMSCs with miR-335 inhibitor treatment before reperfusion, respectively. Blood gases were analyzed during the experiment. Lung tissue wet/dry ratio (W/D), interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), myeloperoxidase (MPO), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured at the end of reperfusion. Mitochondria were observed by electron microscopy and the Flameng scores were counted. Lung histopathology and apoptosis (TUNEL staining) were observed by light microscopy, and the lung injury scores (LIS) and apoptosis index (AI) were detected. The miR-335 expression was detected by RT-qPCR, and the expression of caspase-3, cleaved-caspase-3, caspase-9, cleaved-caspase-9, and NF-κB proteins were detected by Western blot at the end of reperfusion. The results showed that compared with the sham group, the oxygenation index, pH, and base excess (BE) were significantly lower in the IRI group and IRI+PBS group after reperfusion, whereas those indices were significantly higher in the IRI+EXO group than those in the IRI+PBS group (P < 0.05). Compared with the sham group, there were significant increases in W/D, IL-1β, TNF-α, MPO, MDA, LIS, AI, Flameng score, caspase-3, cleaved-caspase-3, caspase-9, and cleaved-caspase-9, however significant decreases in the SOD, miR-335 and NF-κB in the IRI group (P < 0.05). These indices in the IRI and IRI+PBS groups showed no significant differences. Compared with the IRI+PBS group, there were significant decreases in W/D, IL-1β, TNF-α, MPO, MDA, LIS, AI, Flameng score, caspase-3, cleaved-caspase-3, caspase-9, and cleaved-caspase-9, however significant increases in the SOD, miR-335 and NF-κB in the IRI+EXO group (P < 0.05). While, the changes of the above mentioned indices were reversed in the IRI+inhibitor-EXO group compared with IRI+EXO group, which were still better than those in the IRI+PBS group (P < 0.05). The results suggest that BMSCs-EXO could attenuate lung IRI in rats, activate NF-κB pathway, and maintain mitochondrial stability by up-regulating miR-335.

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来源期刊
生理学报
生理学报 Medicine-Medicine (all)
CiteScore
1.20
自引率
0.00%
发文量
4820
期刊介绍: Acta Physiologica Sinica (APS) is sponsored by the Chinese Association for Physiological Sciences and Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences (CAS), and is published bimonthly by the Science Press, China. APS publishes original research articles in the field of physiology as well as research contributions from other biomedical disciplines and proceedings of conferences and symposia of physiological sciences. Besides “Original Research Articles”, the journal also provides columns as “Brief Review”, “Rapid Communication”, “Experimental Technique”, and “Letter to the Editor”. Articles are published in either Chinese or English according to authors’ submission.
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