Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
Tohoku J Exp Med. 2010 Dec;222(4):319-27. doi: 10.1620/tjem.222.319.
Hepatic fibrosis is characterized by excessive accumulation of extracellular matrix. Matrix metalloproteinases (MMPs) play an important role in the remodeling of the extracellular matrix during hepatic fibrosis. Lipocalin-2 (LCN2) forms complexes with MMP-9 and can be detected in the urine of patients with several types of cancers. The objective of this study was to examine the relationship between urinary LCN2 levels and MMP-9 activity with respect to the stage of liver fibrosis in patients with chronic hepatitis C (CHC), and to assess the utility of urine LCN2 as a non-invasive marker of hepatic fibrosis. Fresh spot urine samples were prospectively collected from forty-two interferon-naive CHC patients who underwent liver biopsy. The stage of hepatic fibrosis was assessed according to the METAVIR fibrosis score; 18 patients had no or mild fibrosis (stages F0 and F1) and 24 patients showed significant fibrosis (stages F2-F4). Immunoblot analyses demonstrated co-migration of urine LCN2 and MMP-9. Gelatin zymography showed that urinary MMP-9/MMP-2 activity ratios were higher in patients with significant fibrosis (F2-F4) than in patients no or mild fibrosis (F0-F1). Urine LCN2 levels which were normalized to urine creatinine concentration (urine LCN2-to-creatinine ratio; ULCR) were higher in F2-F4 patients compared to F0-F1 patients. There was a positive correlation between ULCR and urine MMP-9/MMP-2 activity ratios (r = 0.735). ULCR and AST-to-platelet ratio index were independent predictors of significant fibrosis by multivariate analysis. The present study suggests that urinary LCN2 is a novel marker of hepatic fibrosis by reflecting urine MMP-9 activity in CHC.
肝纤维化的特征是细胞外基质的过度积累。基质金属蛋白酶（MMPs）在肝纤维化过程中细胞外基质的重塑中发挥重要作用。脂钙蛋白-2（LCN2）与 MMP-9 形成复合物，并可在几种类型癌症患者的尿液中检测到。本研究的目的是检查慢性丙型肝炎（CHC）患者尿液 LCN2 水平与 MMP-9 活性与肝纤维化分期之间的关系，并评估尿液 LCN2 作为肝纤维化非侵入性标志物的效用。前瞻性收集了 42 名未接受干扰素治疗的 CHC 患者的新鲜尿斑样本来进行研究，这些患者均接受了肝活检。肝纤维化分期根据 METAVIR 纤维化评分进行评估；18 名患者无或轻度纤维化（F0 和 F1 期），24 名患者显示明显纤维化（F2-F4 期）。免疫印迹分析表明尿液 LCN2 和 MMP-9 共迁移。明胶酶谱显示，有明显纤维化（F2-F4）的患者尿液 MMP-9/MMP-2 活性比值高于无或轻度纤维化（F0-F1）的患者。尿液 LCN2 与尿肌酐浓度标准化后的水平（尿液 LCN2-肌酐比值；ULCR）在 F2-F4 患者中高于 F0-F1 患者。ULCR 与尿液 MMP-9/MMP-2 活性比值呈正相关（r=0.735）。多元分析显示，ULCR 和 AST-血小板比值指数是显著纤维化的独立预测因子。本研究表明，尿液 LCN2 通过反映 CHC 患者尿液 MMP-9 活性，是肝纤维化的一种新型标志物。
