骨髓间充质干细胞通过抑制铁死亡改善大鼠重症急性胰腺炎相关肺损伤

doi:10.12092/j.issn.1009-2501.2022.07.001

中国临床药理学与治疗学 ›› 2022, Vol. 27 ›› Issue (7): 721-728.doi: 10.12092/j.issn.1009-2501.2022.07.001

• 基础研究 • 下一篇

骨髓间充质干细胞通过抑制铁死亡改善大鼠重症急性胰腺炎相关肺损伤

余伟迪¹，宋振顺^1,2

¹南京医科大学上海十院临床医学院，上海 200072；²同济大学附属上海市第十人民医院肝外科，上海 200072

收稿日期:2022-05-05 修回日期:2022-07-27 出版日期:2022-07-26 发布日期:2022-08-11
通讯作者: 宋振顺，男，博士，主任医师，博士生导师，研究方向：肝脏移植、肝脏外科研究与基础。 E-mail: zs_song@tongji.edu.cn
作者简介:余伟迪，男，硕士研究生，研究方向：间充质干细胞治疗重症急性胰腺炎。 E-mail: 18351999027@163.com
基金资助:
国家自然科学基金项目（81670582）

Bone marrow-derived mesenchymal stem cells ameliorate severe acute pancreatitis-induced lung injury in rats via suppression of ferroptosis

YU Weidi ¹, SONG Zhenshun^1,2

¹ Department of General Surgery, Shanghai Tenth People's Hospital, Clinical College of Nanjing Medical University, Shanghai 200072, China; ²Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Received:2022-05-05 Revised:2022-07-27 Online:2022-07-26 Published:2022-08-11

摘要/Abstract

摘要： 目的：探讨骨髓间充质干细胞（BMSCs）对重症急性胰腺炎（SAP）大鼠肺组织内细胞铁死亡的抑制作用及其潜在机制。方法：选择3周龄SD雄性大鼠提取、培养BMSCs。将30只6周龄SD雄性大鼠随机分为5组：假手术组（Sham）、胰腺炎组（SAP）、PBS对照组（SAP+PBS）、干细胞治疗组（SAP+BMSCs）、干细胞联合Nrf2阻断剂ML385治疗组（SAP+BMSCs+ML385），每组6只。使用牛磺胆酸钠（NaT）构建大鼠SAP模型。于造模前2 h，SAP+BMSCs+ML385组腹腔注射ML385（5 mg/kg）；于造模后6 h，SAP+BMSCs组和SAP+BMSCs+ML385组尾静脉注射BMSCs（1×107/只），SAP+PBS组尾静脉注射等量的磷酸盐缓冲液（PBS）。3 d后处死大鼠，取胰腺、肺组织和血清。H&E染色观察组织损伤情况。检测血清中淀粉酶、脂肪酶活性和炎症因子水平，肺组织中铁含量、丙二醛（MDA）、谷胱甘肽（GSH）活性。检测肺组织铁响应元件结合蛋白2（IREB2）、铁蛋白重链1（FTH1）、长链脂酰CoA合成酶4（ACSL4）、谷胱甘肽过氧化物酶4（GPX4）、溶质载体家族7成员11（SLC7A11）等铁死亡相关蛋白表达，以及PI3K/AKT/Nrf2通路相关蛋白表达。结果：NaT诱导后大鼠血清淀粉酶、脂肪酶活性、促炎因子水平和病理评分明显升高（P<0.05）。BMSCs移植能够明显减轻上述指标（P<0.05）。相比SAP组，BMSCs治疗组肺组织铁、MDA水平降低，GSH活性升高，IREB2、ACSL4蛋白表达降低，FTH1、GPX4及SLC7A11蛋白表达升高（P<0.05）；ML385能够部分抵消BMSCs移植产生的抗脂质过氧化作用（P<0.05）。BMSCs移植上调了肺组织PI3K、p-AKT总蛋白和Nrf2核蛋白的表达（P<0.05）。结论：BMSCs移植能够有效减轻SAP相关肺损伤的全身炎症反应和局部组织损伤，抑制肺组织铁沉积和脂质过氧化，其抗脂质过氧化作用可能与PI3K/AKT/Nrf2通路有关。

关键词: 间充质干细胞, 重症急性胰腺炎, 肺损伤, 铁死亡

Abstract: AIM: To evaluate the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on ferroptosis in lung injury caused by severe acute pancreatitis (SAP). METHODS: BMSCs were obtained from male SD rats (3 weeks of age). 30 male SD rats (6 weeks of age) were randomly divided into 5 groups: Sham group, SAP group, SAP+PBS group, SAP+BMSCs group, and SAP+BMSCs+ML385 group, with 6 rats in each group. SAP model induced by sodium taurocholate (NaT) was established. Rats in the SAP+MSCs+ML385 group were intraperitoneally injected with ML385 (5 mg/kg) 2h before SAP induction. For PBS control and BMSCs treatment groups, PBS and BMSCs were respectively injected into rats via the tail vein 6 h after creation of the SAP model. All rats were sacrificed 3 days after SAP induction, and pancreas and lung tissue and serum samples were collected. Pancreatic and pulmonary injury was assessed using H&E staining. Serum levels of amylase and lipase and inflammatory factors, as well as tissue levels of iron, malondialdehyde (MDA), glutathione (GSH) were evaluated. The expressions of ferroptosis-associated proteins, including iron responsive element binding protein 2 (IREB2), ferritin heavy chain 1 (FTH1), acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11), as well as the expressions of PI3K/AKT/Nrf2 pathway-related proteins were assessed. RESULTS: The serum levels of amylase, lipase and proinflammatory factors, as well as pathological scores were significantly increased after SAP induction (P<0.05). Changes above were effectively alleviated by BMSCs (P<0.05). Compared with SAP group, the iron and MDA contents were decreased, the GSH activity was increased, the expression of IREB2 and ACSL4 were downregulated and the expression of FTH1, GPX4 and SLC7A11 were upregulated in SAP+BMSCs group (P<0.05). Injection of ML385 partially offset the anti-lipid peroxidation effect of BMSCs (P<0.05). In addition, BMSCs upregulated the total protein levels of PI3K and p-AKT, and the nuclear protein level of Nrf2 in lung tissue (P<0.05). CONCLUSION: BMSCs can effectively reduce systemic inflammatory response and local tissue injury in SAP; BMSCs can inhibit iron deposition and lipid peroxidation in SAP-induced lung injury, and the anti-lipid peroxidation effect may be achieved via activating the PI3K/AKT/Nrf2 signaling pathway.

Key words: mesenchymal stem cells, severe acute pancreatitis, lung injury, ferroptosis

中图分类号:

R657.5

余伟迪, 宋振顺. 骨髓间充质干细胞通过抑制铁死亡改善大鼠重症急性胰腺炎相关肺损伤[J]. 中国临床药理学与治疗学, 2022, 27(7): 721-728.

YU Weidi, SONG Zhenshun. Bone marrow-derived mesenchymal stem cells ameliorate severe acute pancreatitis-induced lung injury in rats via suppression of ferroptosis[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(7): 721-728.

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骨髓间充质干细胞通过抑制铁死亡改善大鼠重症急性胰腺炎相关肺损伤

Bone marrow-derived mesenchymal stem cells ameliorate severe acute pancreatitis-induced lung injury in rats via suppression of ferroptosis

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