慢性丙型肝炎患者肝纤维化进展过程中基质金属蛋白酶的产生与活性
Production and activity of matrix metalloproteinases during liver fibrosis progression of chronic hepatitis C patients.
作者信息
Martinez-Castillo Moises, Hernandez-Barragan Abigail, Flores-Vasconcelos Ivonne, Galicia-Moreno Marina, Rosique-Oramas Dorothy, Perez-Hernandez Jose Luis, Higuera-De la Tijera Fatima, Montalvo-Jave Eduardo E, Torre-Delgadillo Aldo, Cordero-Perez Paula, Muñoz-Espinosa Linda, Kershenobich David, Gutierrez-Reyes Gabriela
机构信息
Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico.
Department of Molecular Biology and Genomics, Institute of Molecular Biology in Medicine and Gene Therapy, Health Science University Center, University of Guadalajara, Guadalajara 06726, Mexico.
出版信息
World J Hepatol. 2021 Feb 27;13(2):218-232. doi: 10.4254/wjh.v13.i2.218.
BACKGROUND
Matrix metalloproteinases (MMPs) participate in the degradation of extracellular matrix compounds, maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver. However, there are few studies on the regulation of liver MMPs in fibrosis progression in humans.
AIM
To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C (CHC).
METHODS
A prospective, cross-sectional, multicenter study was conducted. CHC patients were categorized in fibrosis grades through FibroTest and/or FibroScan . Serum MMP-2, -7, and -9 were determined by western blot and multiplex suspension array assays. Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests. The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated. Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test, whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays.
RESULTS
Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects. MMP-7 distinguished early and advanced stages, with a correlation of 0.32 ( < 0.001), and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4 (area under the receiver operating characteristic, 0.705; 95% confidence interval: 0.605-0.805; < 0.001). Collagenolytic activity was detected at F0 and F1, whereas gelatinase activity was not detected at any fibrosis stage. Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2 ( < 0.001).
CONCLUSION
High concentrations of inactive MMPs were present in the serum of CHC patients, reflecting the impossibility to restrain liver fibrosis progression. MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.
背景
基质金属蛋白酶（MMPs）参与细胞外基质化合物的降解，维持肝脏中纤维生成和纤维溶解过程之间的稳态。然而，关于人类肝纤维化进展过程中肝脏MMPs的调节研究较少。
目的
评估慢性丙型肝炎（CHC）肝纤维化各阶段基质金属蛋白酶的产生活性及调节情况。
方法
进行了一项前瞻性、横断面、多中心研究。通过FibroTest和/或FibroScan对CHC患者进行纤维化分级。采用蛋白质印迹法和多重悬浮阵列分析法测定血清MMP-2、-7和-9。通过Kruskal-Wallis检验和Mann-Whitney U检验验证差异。计算Spearman相关系数和受试者工作特征曲线下面积。通过偶氮胶原底物和酶谱试验测定胶原酶活性和明胶酶活性，而通过斑点印迹法测定金属蛋白酶组织抑制剂-1的产生情况。
结果
CHC患者血清中所评估的MMPs浓度高于健康受试者。MMP-7可区分早期和晚期阶段，相关性为0.32（P<0.001），受试者工作特征曲线下面积显示MMP-7在F4期具有中等敏感性和特异性（受试者工作特征曲线下面积，0.705；95%置信区间：0.605-0.805；P<0.001）。在F0和F1期检测到胶原酶活性，而在任何纤维化阶段均未检测到明胶酶活性。金属蛋白酶组织抑制剂-1测定显示在F0和F1期上调，但在F2期下调（P<0.001）。
结论
CHC患者血清中存在高浓度的无活性MMPs，这反映出无法抑制肝纤维化进展。MMPs可能是改善CHC肝纤维化逆转新策略的良好诊断候选物和治疗靶点。
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