| 陆霓虹,杜映荣,刘洪璐,陈杨君,杨永锐.七种不同基质金属蛋白酶在抗结核药物性肝损伤小鼠模型中的表达与临床价值[J].中国医药导报,2024,21(4):6-10 |
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| 七种不同基质金属蛋白酶在抗结核药物性肝损伤小鼠模型中的表达与临床价值 |
| Expression and clinical value of seven different matrix metalloproteinases in anti-tuberculosis drug- induced liver injury mouse model |
| 收稿日期： 修订日期：2023-04-11 |
| DOI：10.20047/j.issn1673-7210.2024.04.02 |
| 关键词: 基质金属蛋白酶2 基质金属蛋白酶7 基质金属蛋白酶9 抗结核药物性肝损伤 小鼠模型 |
| Key Words: |
| 基金项目:国家自然科学基金委员会地区科学基金项目（81960096）；云南省科技厅科技计划项目地方高校联合专项（202001BA070001-134）；云南省教育厅科学研究基金教师类项目（2023J0916） |
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| 摘要:目的 探讨7种不同基质金属蛋白酶（MMP）在抗结核药物性肝损伤小鼠模型中的表达与临床价值。 方法 选取120只雄性昆明小鼠，SPF级，6周龄，体重18～24 g，随机区组法分为6组，每组20只。一组设为对照组，五组感染结核分枝杆菌后分别灌胃异烟肼（INH）45 mg/（kg·d）（INH组）、利福平（RIF）90 mg/（kg·d）（RIF组）、乙胺丁醇（EB）135 mg/（kg·d）（EB组）、吡嗪酰胺（PZA）180 mg/（kg·d）（PZA组）、四联抗结核药（INH+RIF+EB+PZA）剂量同上（四联药组），建立抗结核药物性肝损伤小鼠模型。通过酶联免疫吸附试验法检测药物灌胃后12 h及1、2、3周小鼠模型血清中MMP-1、2、3、7、9、13、14的表达水平，分析其与肝脏指数变化的相关性，探讨不同MMP在抗结核药物性肝损伤中的作用。 结果 给药12 h，与对照组比较，RIF组MMP-7表达上调，差异有统计学意义（P＜0.05）。各组MMP-1、2、3、9、13、14，肝脏指数比较，差异无统计学意义（P＞0.05）。连续灌胃1周，与对照组比较，INH组、RIF组和四联药组小鼠MMP-2和MMP-7表达上调，肝脏指数升高，差异有统计学意义（P＜0.05）；各组MMP-1、3、9、13、14，肝脏指数，与对照组比较，差异无统计学意义（P＞0.05）。连续灌胃药物2、3周后，与对照组比较，RIF组、INH组、四联药组小鼠血清MMP-2、7、9表达上调，肝脏指数升高，差异有统计学意义（P＜0.05）；各组其他MMPs表达水平和肝脏指数与对照组比较，差异无统计学意义（P＞0.05）。INH组MMP-2、7、9与肝脏指数无相关性（P＞0.05），四联药组MMP-2、7、9与肝脏指数无相关性（P＞0.05）。RIF组MMP-7与肝脏指数呈正相关（r=0.981，P＜0.05）。 结论 抗结核药物性肝损伤小鼠血清MMP-2、MMP-7和MMP-9明显升高，提示MMP-2、MMP-7和MMP-9介导的炎症反应与抗结核药物性肝损伤密切相关，其中MMP-7可用于预判抗结核药物性肝损伤严重程度。 |
| Abstract:Objective To explore the expression and clinical value of seven different matrix metalloproteinase (MMP) in mouse model of anti-tuberculosis drug induced liver injury. Methods A total of 120 male Kunming species mice, SPF grade, 6 weeks old, weight 18-24 g, were divided into six groups, with 20 mice in each group by random block methe. One group was set as the control group, after infection with Mycobacterium tuberculosis, the five groups were intragaically treated with Isoniazid (INH) 45 mg/(kg·d) (INH group), Rifampicin (RIF) 90 mg/(kg·d) (RIF group), Ethambutol (EB) 135 mg/(kg·d) (EB group), and Pyrazinamide (PZA) 180 mg/(kg·d) (PZA group) respectively. The dose of four anti-tuberculosis durg was the same as above (quadruple drug group) to establish a mouse model of anti-tuberculosis drug-induced liver injury. The expression levels of MMP-1, 2, 3, 7, 9, 13, and 14 in serum of mouse models were detected by enzyme-linked immunosorbent assay at 12 h, 1, 2 and 3 weeks after drug administration, and their correlation with liver index changes were analyzed to explore the role of different MMP in anti-tuberculosis drug-induced liver injury. Results After 12 h of administration, compared with control group, the expression of MMP-7 in RIF group was up-regulated, with statistical significance (P＜0.05). There was no significant difference in liver index of MMP-1, 2, 3, 9, 13, 14 among all groups (P＞0.05). Compared with the control group, the expressions of MMP-2 and MMP-7 in INH group, RIF group, and quadruple drug group were up-regulated, and the liver index was increased, with statistical significances (P＜0.05). There was no significant difference in expressions of MMP-1, 3, 9, 13, 14, and liver index between groups compared with control group (P＞0.05). After 2 and 3 weeks of continuous administration of the drug, compared with the control group, the expressions of MMP-2, 7 and MMP-9 in serum of mice in RIF group, INH group, and quadruple drug groups were upregulated, and the liver index was increased, with statistical significances (P＜0.05). There was no significant difference in the expression level of other MMP and liver index among all groups compared with the control group (P＞0.05). There was no correlation between expressions of MMP-2, 7, 9, and liver index in INH group (P＞0.05), while there was no correlation between MMP-2, 7, 9 and liver index in the quadruple drug group (P＞0.05). There was a positive correlation between MMP-7 and liver index in RIF group (r= 0.981, P＜0.05). Conclusion The serum levels of MMP-2, 7, and MMP-9 in mice with anti-tuberculosis drug induced liver injury are significantly elevated, indicating that the inflammatory response mediated by MMP-2, MMP-7, and MMP-9 is closely related to anti-tuberculosis drug induced liver injury. MMP-7 can be used to predict the severity of anti-tuberculosis drug induced liver injury. |
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