中国临床药理学杂志

西罗莫司联合环孢素A对再生障碍性贫血小鼠的影响

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林丽屏 ^1a , 陈登云 ^1b , 庄燕玲 ^1a , 王明泉 ^1a

中国临床药理学杂志 | 临床与基础桥接研究 2025,41(9): 1268-1274

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中国临床药理学杂志 |临床与基础桥接研究 2025 , 41 (9) : 1268 -1274

西罗莫司联合环孢素A对再生障碍性贫血小鼠的影响

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林丽屏^1a, 陈登云^1b, 庄燕玲^1a, 王明泉^1a

作者信息

^1a.福建省泉州市第一医院，输血科，福建泉州 362000

^1b.福建省泉州市第一医院，检验科，福建泉州 362000

通讯作者:

王明泉，主任技师 Tel: （0595）22277127 E-mail: 108515059@qq.com

作者简介:

林丽屏（1984-），女，主管技师，主要从事输血技术与治疗，血液疾病方面的研究

Effects of rapamycin combined with cyclosporin A on mice with aplastic anemia

Li-ping LIN^1a, Deng-yun CHEN^1b, Yan-ling ZHUANG^1a, Ming-quan WANG^1a

Affiliations

^1a.Department of Blood Transfusion, Quanzhou First Hospital, Quanzhou 362000, Fujian Province, China

^1b.Department of Laboratory, Quanzhou First Hospital, Quanzhou 362000, Fujian Province, China

出版时间: 2025-05-17 doi: 10.13699/j.cnki.1001-6821.2025.09.012

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摘要

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目的

探究西罗莫司（RAP）联合环孢素A（CsA）通过调控T盒转录因子（T-bet）/干扰素-γ（IFN-γ）信号通路对再生障碍性贫血小鼠造血功能及骨髓内皮生长因子（VEGF）、血小板生成素（TPO）和血管细胞黏附因子-1（VCAM-1）水平的影响。

方法

将纯系雌性昆明小鼠随机分为对照组（不做任何处理）、模型组（皮下注射50 mg·kg^-1环磷酰胺，隔天1次，共4次；同时吸入30 mg·L^-1甲苯，每天1次，连续8 d）、CsA组（在模型组基础上腹腔注射5 mg·kg^-1 CsA）、RAP-L联合CsA组（在模型组基础上腹腔注射5 mg·kg^-1 CsA和0.1 mg·kg^-1 RAP）、RAP-M联合CsA组（在模型组基础上腹腔注射5 mg·kg^-1 CsA和0.5 mg·kg^-1 RAP）、RAP-H联合CsA组（在模型组基础上腹腔注射5 mg·kg^-1 CsA和1 mg·kg^-1 RAP）、RAP-H组（在模型组基础上腹腔注射1 mg·kg^-1 RAP），每组各10只，除对照组外，其余各组均建立再生障碍性贫血模型。用生化分析仪检测外周血红细胞（RBC）、白细胞、血红蛋白和血小板水平，用苏木精-伊红染色观察骨髓形态并进行病理损伤评分，用酶联免疫吸附试验法检测骨髓上清液中VEGF、VCAM-1、TPO、IFN-γ和肿瘤坏死因子-α水平，用免疫组化法检测TPO表达水平，用实时荧光定量聚合酶链反应和蛋白质印迹法检测骨髓单个核细胞T-bet的信使核糖核酸（mRNA）和蛋白表达水平。

结果

对照组、模型组、CsA组、RAP-H联合CsA组和RAP-H组的RBC水平分别为（8.48±0.89）×10¹²、（2.14±0.25）×10¹²、（3.54±0.54）×10¹²、（6.12±0.74）×10¹²、（3.26±0.61）×10¹²·L^-1，病理损伤评分分别为（0.20±0.04）、（2.50±0.25）、（1.10±0.10）、（1.00±0.11）和（1.20±0.16）分，TPO水平分别为（195.48±28.15）、（145.81±15.24）、（169.76±20.26）、（190.54±22.37）和（165.52±20.29）pg·mL^-1，VCAM-1水平分别为（213.46±32.33）、（132.81±21.94）、（185.49±19.65）、（204.19±19.82）和（183.67±20.87）ng·mL^-1，IFN-γ水平分别为（132.04±18.10）、（232.46±25.29）、（205.98±21.26）、（183.67±20.20）和（209.05±19.82）pg·mL^-1，T-bet mRNA相对表达水平分别为1.00±0.10、3.98±0.69、2.18±0.21、1.95±0.20和2.24±0.23，T-bet蛋白相对表达水平分别为1.00±0.10、2.46±0.29、1.98±0.21、1.67±0.20和2.01±0.22。模型组的上述指标与对照组比较，CsA组、RAP-H联合CsA组、RAP-H组的上述指标与模型组比较，RAP-H联合CsA组的上述指标与CsA组和RAP-H组比较，在统计学上差异均有统计学意义（均P<0.05）。

结论

CsA联合RAP可以明显改善再生障碍性贫血模型小鼠的造血功能及细胞免疫功能，可能与提高骨髓TPO和VCAM-1水平，调节T-bet/IFN-γ信号通路有关。

关键词

环孢素A / 西罗莫司 / 再生障碍性贫血 / 造血功能 / T盒转录因子 / 干扰素-γ

Abstract

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Objective

To explore the effects of rapamycin (RAP) combined with cyclosporine A (CsA) on the hematopoietic function and the levels of bone marrow vascular endothelial growth factor (VEGF), thrombopoietin (TPO), and vascular cell adhesion molecule-1 (VCAM-1) in aplastic anemia mice by regulating the T-box transcription factor (T-bet)/interferon-gamma (IFN-γ) signaling pathway.

Methods

Female Kunming mice of pure line were randomly divided into control group (without any treatment), model group (subcutaneously injected with 50 mg·kg^-1 cyclophosphamide, once every other day for a total of 4 times; meanwhile, inhaling 30 mg·L^-1 toluene once a day for 8 consecutive days), CsA group (intraperitoneally injected with 5 mg·kg^-1 CsA on the basis of the model group), RAP-L combined with CsA group (intraperitoneally injected with 5 mg·kg^-1 CsA and 0.1 mg·kg^-1 RAP on the basis of the model group), RAP-M combined with CsA group (intraperitoneally injected with 5 mg·kg^-1 CsA and 0.5 mg·kg^-1 RAP on the basis of the model group), RAP-H combined with CsA group (intraperitoneally injected with 5 mg·kg^-1 CsA and 1 mg·kg^-1 RAP on the basis of the model group), and RAP-H group (intraperitoneally injected with 1 mg·kg^-1 RAP on the basis of the model group), with 10 mice in each group. Except for the control group, the aplastic anemia model was established in the other groups. A biochemical analyzer was used to detect the levels of peripheral blood red blood cells (RBC), white blood cells, hemoglobin and platelets. Hematoxylin-eosin staining was used to observe the bone marrow morphology and conduct pathological injury scoring. The enzyme-linked immunosorbent assay method was used to detect the levels of VEGF, VCAM-1, TPO, IFN-γ and tumor necrosis factor-α in the bone marrow supernatant. Immunohistochemistry was used to detect the expression of TPO. Real-time fluorescence quantitative polymerase chain reaction and Western blotting were used to detect the messenger ribonucleic acid (mRNA) and protein expressions of T-bet in bone marrow mononuclear cells.

Results

The RBC levels of the control group, model group, CsA group, RAP-H combined with CsA group and RAP-H group were (8.48±0.89)×10¹², (2.14±0.25)×10¹², (3.54±0.54)×10¹², (6.12±0.74)×10¹² and (3.26±0.61) ×10¹²·L^-1, respectively; the pathological injury scores were (0.20±0.04), (2.50±0.25), (1.10±0.10), (1.00±0.11) and (1.20±0.16) points, respectively; the TPO levels were (195.48±28.15), (145.81±15.24), (169.76±20.26), (190.54±22.37) and (165.52±20.29) pg·mL^-1, respectively; the VCAM-1 levels were (213.46±32.33), (132.81±21.94), (185.49±19.65), (204.19±19.82) and (183.67±20.87) ng·mL^-1, respectively; the IFN-γ levels were (132.04±18.10), (232.46±25.29), (205.98±21.26), (183.67±20.20) and (209.05±19.82) pg·mL^-1, respectively; the relative expression levels of T-bet mRNA were 1.00±0.10, 3.98±0.69, 2.18±0.21, 1.95±0.20 and 2.24±0.23, respectively; the relative expression levels of T-bet protein were 1.00±0.10, 2.46±0.29, 1.98±0.21, 1.67±0.20 and 2.01±0.22, respectively. When the above-mentioned indicators of the model group were compared with those of the control group, the above-mentioned indicators of the CsA group, the RAP-H combined with CsA group, and the RAP-H group were compared with those of the model group, and the above-mentioned indicators of the RAP-H combined with CsA group were compared with those of the CsA group and the RAP-H group, all the differences were statistically significant (all P<0.05).

Conclusion

CsA combined with RAP can significantly improve the hematopoietic function and cellular immune function of aplastic anemia model mice, which may be related to increasing the levels of bone marrow TPO and VCAM-1 and regulating the T-bet/IFN-γ signaling pathway.

Key words

cyclosporine A / rapamycin / aplastic anemia / hematopoietic function / T-box transcription factors / interferon-γ

引用本文

林丽屏, 陈登云, 庄燕玲, 王明泉. 西罗莫司联合环孢素A对再生障碍性贫血小鼠的影响. 中国临床药理学杂志, 2025 , 41 (9) : 1268 -1274 . DOI: 10.13699/j.cnki.1001-6821.2025.09.012

Li-ping LIN, Deng-yun CHEN, Yan-ling ZHUANG, Ming-quan WANG. Effects of rapamycin combined with cyclosporin A on mice with aplastic anemia[J]. Chinese Journal of Clinical Pharmacology, 2025 , 41 (9) : 1268 -1274 . DOI: 10.13699/j.cnki.1001-6821.2025.09.012

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2025年第41卷第9期

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doi: 10.13699/j.cnki.1001-6821.2025.09.012

接收时间：2024-12-29
首发时间：2026-08-04
出版时间：2025-05-17

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收稿日期：2024-12-29

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^1a.福建省泉州市第一医院，输血科，福建泉州 362000

^1b.福建省泉州市第一医院，检验科，福建泉州 362000

通讯作者:

王明泉，主任技师 Tel: （0595）22277127 E-mail: 108515059@qq.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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