Clinical Evaluation of Immune Function and SAA, MMP-9 and MMP-14 in Liver Injury Caused by Anti-Tuberculous Drugs
-
摘要:
目的 探讨抗结核药物性肝损伤患者免疫功能变化，及血清淀粉蛋白酶A（serum amylase A，SAA）和基质金属蛋白酶9（matrix metalloproteinase 9，MMP-9）、基质金属蛋白酶14（matrix metalloproteinase 14，MMP-14）在抗结核药物性肝损伤（anti-tuberculosis drug-induced liver injury，ATB-DILI）中的临床价值和应用意义。 方法 选取2019年7月至2020年7月昆明市第三人民医院收治的抗结核药物性肝损伤患者115例，根据肝损伤不同类型，将患者分为A、B、C、D 4个亚组，选取同期健康体检者35例设为对照组（E组）。比较免疫功能和SAA、MMP-9、MMP-14在不同亚组的变化及表达水平，以及与ATB-DILI严重程度分级之间的关系。 结果 A组患者CD4+T淋巴细胞计数低于E组，两两比较，差异具有统计学意义（P < 0.05）；SAA与MMP-9的表达量高于其他3组，组间差异有统计学意义（P < 0.05）；C组患者MMP-14的表达量高于其他3组，差异具有统计学意义（P < 0.05）。SAA和MMP-9与ATB-DILI严重程度分级具有相关关系（r = 0.687，P < 0.05；r = 0.811，P < 0.05）。 结论 CD4+T淋巴细胞在部分ATB-DILI患者中有所降低，提示该类患者存在免疫功能低下，免疫屏障受损可能与肝损伤有一定相关性。SAA、MMP-9和MMP-14在不同肝损伤类型患者中均有程度不一的升高，ATB-DILI严重程度与SAA和MMP-9的表达量密切相关，SAA和MMP-9、MMP-14有望成为临床ATB-DILI严重程度的评估指标。 Abstract:Objective To explore the changes of immune function in patients with anti-tuberculous drug-induced liver injury （ATB-DILI）, and to explore the clinical value and application significance of serum amylase A （SAA）, matrix metalloproteinase 9 （MMP-9） and matrix metalloproteinase 14 （MMP-14） in anti-tuberculosis drug liver injury. Methods A total of 115 patients with anti-tuberculosis drug-induced liver injury admitted to the Third People’ s Hospital of Kunming from July 2019 to July 2020 were selected. Based on types of liver injury, the patients were divided into 4 subgroups A, B, C and D, and 35 healthy subjects underwent health check during the same period were selected as control group （group E）. The changes and expression levels of immune function, SAA, MMP-9 and MMP-14 in different subgroups were compared, as well as their relationship with ATB-DILI severity grade. Results The CD4+ count of group A patients was lower than that of group E, and the difference was statistically significant （P < 0.05）. The expression levels of SAA and MMP-9 in gronp A were higher than the other three groups, and the difference between the groups was statistically significant （P < 0.05）. The expression of MMP-14 in group C was higher than that of the other three groups, and the difference was statistically significant （P < 0.05）. SAA and MMP-9 were correlated with the severity of anti-tuberculosis drug liver injury （r = 0.687, P < 0.05; r = 0.811, P < 0.05）. Conclusion CD4+ counts were reduced in some patients with ATB-DILI, suggesting that these patients have low immune function, and the impaired immune function may be related to liver injury. SAA, MMP-9 and MMP-14 increased in different degrees in patients with different types of anti-tuberculosis drug liver injury. The severity of liver injury is closely related to the expression of SAA and MMP-9. SAA, MMP-9 and MMP-14 are expected to be the evaluation indicators of the severity of clinical ATB-DILI. -
表 1 一般资料比较（
$ \bar x \pm s $ ）Table 1. Comparison of general information （
$\bar x \pm s $ ）项目 年龄（岁） 身高（cm） 体重（kg） 体质指数（kg/cm2） A组（n = 67） 39.1 ± 11.2 169.1 ± 5.7 57.3 ± 12.4 21.2 ± 2.3 B组（n = 17） 42.0 ± 7.0 167.2 ± 5.9 61.2 ± 11.7 19.8 ± 2.2 C组（n = 18） 37.1 ± 7.6 171.2 ± 6.6 60.5 ± 11.3 20.4 ± 2.1 D组（n = 13） 45.1 ± 8.2 166.2 ± 7.1 59.2 ± 9.7 20.1 ± 2.4 E组（n = 35） 34.1 ± 8.6 170.2 ± 6.1 67.2 ± 8.5 22.3 ± 1.3 F 0.349 0.647 0.672 0.565 P 0.943 0.633 0.541 0.690 
下载: 导出CSV
表 2 T淋巴细胞亚群细胞计数比较（
$ \bar x \pm s $ ）Table 2. Comparison of cell counts of T lymphocyte subsets （
$ \bar x \pm s $ ）项目 CD3计数（个） CD4计数（个） CD8计数（个） A组（n=67） 719 ± 110 455 ± 116 476 ± 89 B组（n = 17） 674 ± 89 566 ± 122 527 ± 87 C组（n = 18） 621 ± 78 521 ± 78 515 ± 103 D组（n = 13） 697 ± 82 559 ± 90 501 ± 91 E组（n = 35） 914 ± 170 810 ± 158 513 ± 85 F 0.775 6.784 0.446 P 0.550 0.000* 0.775 *P < 0.05。
下载: 导出CSV
表 3 不同亚组SAA、MMP-9、MMP-14的比较（
$\bar x \pm s $ ）Table 3. Comparison of SAA，MMP-9 and MMP-14 in different groups （
$\bar x \pm s $ ）项目 SAA（mg/L） MMP-9（ng/mL） MMP-14（ng/mL） A组（n = 67） 89.1 ± 11.2 36.1 ± 10.2 5.2 ± 3.3 B组（n = 17） 32.3 ± 6.1 11.3 ± 6.2 6.0 ± 2.6 C组（n = 18） 47.5 ± 9.2 14.1 ± 7.1 11.2 ± 6.9 D组（n = 13） 55.2 ± 11.3 15.3/12.5 4.0 ± 2.1 F 4.432 5.414 3.996 P 0.012# 0.005# 0.018# #P < 0.05。
下载: 导出CSV
表 4 SAA、MMP-9、MMP-14与肝损伤严重程度的比较（
$ \bar x \pm s $ ）Table 4. Comparison of SAA，MMP-9，MMP-14 and the severity of liver injury （
$ \bar x \pm s $ ）项目 1级（n = 41） 2级（n = 32） 3级（n = 25） 4级（n = 15） 5级（n = 2） Spearman系数（r） P SAA（mg/L） 26.1 ± 13.1 45.3 ± 15.2 69.2 ± 19.1 115.0 ± 21.3 146.0 ± 28.4 0.687# 0.001# MMP-9（ng/mL） 11.4 ± 5.1 39.1 ± 11.2 45.2 ± 10.4 55.1 ± 9.3 65.3 ± 21.1 0.811* 0.000* MMP-14（ng/mL） 3.61 ± 1.5 4.0 ± 1.2 4.01 ± 1.3 6.54 ± 2.3 8.21 ± 3.6 0.075 0.141 # P < 0.05，*P < 0.001。
下载: 导出CSV
-
[1] 迟旭,漆沄,陈娟,等. 初次抗结核治疗诱发药物性肝损伤临床特点及发病危险因素的Logistic回归分析[J]. 陕西医学,2019,48(1):67-70. [2] 中国中西医结合学会检验医学专业委员会. 血清淀粉样蛋白A在感染性疾病中临床应用的专家共识[J]. 中华检验医学杂志,2019,42(3):186-192. [3] 刘明明,李爱玲,修瑞娟. 基质金属蛋白酶的研究进展[J]. 中国病理生理杂志,2018,34(10):1914-1920. doi: 10.3969/j.issn.1000-4718.2018.10.029 [4] 周志亮,王淳良. 基质金属蛋白酶-9在胶质瘤中的研究进展[J]. 健康必读,2021,16(1):259-260. [5] 中华医学会结核病学分会. 抗结核药物性肝损伤诊治指南(2019年版)[J]. 中华结核和呼吸杂志,2019,36(10):343-356. [6] 中华人民共和国国家卫生和计划生育委员会. wS288～2017肺结核诊断[S]. 北京: 人民卫生出版社, 2017. [7] 孟佩佩,刘世坤,何阳,等. 144例药物性肝损伤的临床特点及影响因素分析[J]. 中国临床药理学杂志,2017,33(5):467-469. [8] 吴于清,钟诚,黄燕群,等. CD4+CD25+调节性T细胞在抗结核药物所致的肝损伤中的作用[J]. 结核病与肝部健康杂志,2017,6(2):125-127. [9] 马小云,白满灵. 113例抗结核药物致患者药物性肝损伤临床观察[J]. 药学研究,2020,49(2):82-84. [10] 刘成刚,谢恬,张坤江,等. 新疆维吾尔族、汉族抗结核药物性肝损伤患者NO及NOS表达水平的研究[J]. 中国感染控制杂志,2018,17(4):283-288. doi: 10.3969/j.issn.1671-9638.2018.04.002 [11] 黄洁,王晖,周蜜. T淋巴细胞亚群在抗结核药物所致肝损伤中的作用[J]. 江西医药,2018,53(4):393-394. doi: 10.3969/j.issn.1006-2238.2018.4.039 [12] 王贺,李仕来,朱继金. 细胞自噬在脓毒症肝损伤中的研究进展[J]. 中国急救医学,2021,41(1):87-90. doi: 10.3969/j.issn.1002-1949.2021.01.017 [13] 陶叶海. 抗结核急性药物性肝损伤患者外周血CD8+T细胞上CD28表达及意义[J]. 上海预防医学,2014,26(11):626-628. [14] Sack G H,Jr. Serum amyloid A - a review[J]. Mol Med,2018,24(1):1-27. doi: 10.1186/s10020-018-0047-0 [15] Yuzhalin A E,Lim S Y,Kutikhin A G,et al. Dynamic matrisome:ECM remodeling factors licensing cancer progression and metastasis[J]. Biochim Biophys Acta Rev Cancer,2018,1870(2):207-228. doi: 10.1016/j.bbcan.2018.09.002 [16] 吴启文,陈玉成. 门冬氨酸鸟氨酸联合异甘草酸镁治疗抗结核药所致药物性肝损伤临床研究[J]. 岭南急诊医学杂志,2020,25(3):243-245. doi: 10.3969/j.issn.1671-301X.2020.03.012 [17] 孙勤,肖和平. 抗结核药物所致肝损伤分子遗传机制的探讨[J]. 中华结核和呼吸杂志,2018,41(1):10. doi: 10.3760/cma.j.issn.1001-0939.2018.01.005 [18] 徐杨,熊英琼. 基质金属蛋白酶9和血管内皮生长因子对缺血性脑卒中的影响[J]. 中国医药导报,2020,17(3):41-44. [19] De Buck M,Gouwy M,Wang J M,et al. Structure and expression of different serum amyloid A (SAA) variants and their concentration-dependent functions during host insults[J]. Curr Med Chem,2016,23(17):1725-1755. doi: 10.2174/0929867323666160418114600 [20] 刘朋. 急性脑卒中患者血清MMP-9、Hcy及Lp(a)水平变化及临床意义分析[J]. 实用中西医结合临床,2021,21(6):123-124. [21] Cui G,Cai F,Ding Z,et al. MMP14 predicts a poor prognosis in patients with colorectal cancer[J]. Hum Pathol,2019,83(18):36-42. [22] 杨涛,苏忠,杨奕,等. 肝细胞癌组织中基质金属蛋白酶14的表达及其与预后的关系[J]. 东南大学学报(医学版),2021,40(1):63-68. doi: 10.3969/j.issn.1671-6264.2021.01.012 [23] Xiao G,Wang P,Zheng X,et al. FAM83A-AS1 promotes lung adenocarcinoma cell migration and invasion by targeting miR-150-5p and modifying MMP14[J]. Cell Cycle,2019,18(21):2972-2985. doi: 10.1080/15384101.2019.1664225 [24] 吐尔逊江·艾力,曹国磊,陈慧芳,等. miR-9和MMP-14在非小细胞肺癌中的表达及临床意义[J]. 临床肿瘤学杂志,2021,26(6):554-558. doi: 10.3969/j.issn.1009-0460.2021.06.013 [25] Filipe E C,Chitty J L,Cox T R. Charting the unexplored extracellular matrix in cancer[J]. Int J Exp Pathol,2018,99(2):58-76. doi: 10.1111/iep.12269 -
