Zhang Bing, Meng Chao, Quan Lini, Duan Le, Kang Jiyu, Zhou Huacheng
Department of Pain, Fourth Affiliated Hospital of Harbin Medical University, No. 37, Yiyuan Street, Nangang District, Harbin City, Hei Longjiang Province, 150001, China.
Department of Pain Management, Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
Drug Deliv Transl Res. 2025 Apr 3. doi: 10.1007/s13346-025-01844-6.
Lung ischemia-reperfusion injury (IRI) is a clinically challenging problem. Exosomes (EXOs) derived from bone marrow mesenchymal stem cells (BMSC-EXOs) can alleviate multiple organs IRI, but few reports on lung IRI. MiRNA-335 is a kind of miRNA in EXOs, which was also shown protective effects on lung IRI. This study hypothesizes that BMSC-EXOs might alleviate lung IRI through miRNA-335, and further to explore its mechanism. The Sprague-Dawley male rats were divided into sham, IRI, phosphate buffer saline (PBS), and EXO groups (n = 6). In the sham group, rats were underwent anesthesia without IRI model establishment. In the IRI, PBS, and EXO groups, rats were established lung IRI model and with no treatment, 30 µl PBS, or 20 µg EXOs (in 30 µl PBS), respectively. The miRNA-335 inhibitor and miRNA-335 mimic processed EXOs were also given to observe the effects of miRNA-335. The oxidative index, lung static compliance, inflammation response, oxidative stress injury, apoptosis, and mitochondrial were observed. The expression of miRNA-335 and silent matching type information regulation 2 homolog 3 (SIRT3) were also detected. The oxidative index, lung static compliance, inflammation response, oxidative stress injury, apoptosis, and mitochondrial injury were significantly deteriorated in the IRI group compared with those in the sham group, while those indicators have significantly improved in the EXO group, and the miRNA-335 and SIRT3 expressions increased (P < 0.05). And the miRNA-335 inhibitor processed EXOs suppressed the SIRT3 expression significantly, but the miRNA-335 mimic processed EXOs enhanced the SIRT3 expression significantly (P < 0.05). In conclusion, BMSC-EXOs maintained mitochondrial structural stability, and alleviated rat lung IRI by inhibiting lung inflammation, oxidative stress injury, and apoptosis, improved lung oxygenation capacity and static compliance, which might be achieved through the miRNA335/SIRT3 pathway.
肺缺血再灌注损伤（IRI）是一个具有临床挑战性的问题。源自骨髓间充质干细胞的外泌体（BMSC-EXOs）可减轻多器官IRI，但关于肺IRI的报道较少。MiRNA-335是外泌体中的一种miRNA，也显示出对肺IRI的保护作用。本研究假设BMSC-EXOs可能通过miRNA-335减轻肺IRI，并进一步探索其机制。将Sprague-Dawley雄性大鼠分为假手术组、IRI组、磷酸盐缓冲盐水（PBS）组和EXO组（n = 6）。假手术组大鼠接受麻醉但未建立IRI模型。在IRI组、PBS组和EXO组中，大鼠分别建立肺IRI模型且不进行治疗、给予30 μl PBS或20 μg EXOs（溶于30 μl PBS中）。还对经过miRNA-335抑制剂和miRNA-335模拟物处理的EXOs进行给药，以观察miRNA-335的作用。观察氧化指标、肺静态顺应性、炎症反应、氧化应激损伤、细胞凋亡和线粒体情况。还检测了miRNA-335和沉默匹配型信息调节2同源物3（SIRT3）的表达。与假手术组相比，IRI组的氧化指标、肺静态顺应性、炎症反应、氧化应激损伤、细胞凋亡和线粒体损伤显著恶化，而EXO组的这些指标显著改善，且miRNA-335和SIRT3表达增加（P < 0.05）。并且经过miRNA-335抑制剂处理的EXOs显著抑制了SIRT3表达，但经过miRNA-335模拟物处理的EXOs显著增强了SIRT3表达（P < 0.05）。总之，BMSC-EXOs维持线粒体结构稳定性，通过抑制肺炎症、氧化应激损伤和细胞凋亡减轻大鼠肺IRI，改善肺氧合能力和静态顺应性，这可能是通过miRNA335/SIRT3途径实现的。
