University of Padova, Dept. Biomedical Sciences, 35121, Padova, Italy.
University of Padova, Dept. of Surgery, Oncology and Gastroenterology, 35124, Padova, Italy.
Sci Rep. 2017 Nov 2;7(1):14956. doi: 10.1038/s41598-017-14946-0.
The heparan sulfate endoglycosidase heparanase (HPSE) is involved in tumor growth, chronic inflammation and fibrosis. Since a role for HPSE in chronic liver disease has not been demonstrated to date, the current study was aimed at investigating the involvement of HPSE in the pathogenesis of chronic liver injury. Herein, we revealed that HPSE expression increased in mouse livers after carbon tetrachloride (CCl)-mediated chronic induction of fibrosis, but with a trend to decline during progression of the disease. In mouse fibrotic liver tissues HPSE immunostaining was restricted in necro-inflammatory areas, co-localizing with F4/80 macrophage marker and TNF-α. TNF-α treatment induced HPSE expression as well as HPSE secretion in U937 macrophages. Moreover, macrophage-secreted HPSE regulated the expression of α-SMA and fibronectin in hepatic stellate LX-2 cells. Finally, HPSE activity increased in the plasma of patients with liver fibrosis but it inversely correlated with liver stiffness. Our results suggest the involvement of HPSE in early phases of reaction to liver damage and inflammatory macrophages as an important source of HPSE. HPSE seems to play a key role in the macrophage-mediated activation of hepatic stellate cells (HSCs), thus suggesting that HPSE targeting could be a new therapeutic option in the treatment of liver fibrosis.
硫酸乙酰肝素内切糖苷酶（HPSE）参与肿瘤生长、慢性炎症和纤维化。由于迄今为止尚未证明 HPSE 在慢性肝病中的作用，本研究旨在研究 HPSE 在慢性肝损伤发病机制中的作用。本研究揭示，四氯化碳（CCl）介导的慢性纤维化诱导后，HPSE 在小鼠肝脏中的表达增加，但在疾病进展过程中呈下降趋势。在小鼠纤维化肝组织中，HPSE 免疫染色局限于坏死性炎症区域，与 F4/80 巨噬细胞标志物和 TNF-α共定位。TNF-α 处理诱导 U937 巨噬细胞中 HPSE 的表达和分泌。此外，巨噬细胞分泌的 HPSE 调节肝星状细胞 LX-2 中 α-SMA 和纤维连接蛋白的表达。最后，肝纤维化患者的血浆中 HPSE 活性增加，但与肝硬度呈负相关。我们的结果表明 HPSE 参与了对肝损伤和炎症性巨噬细胞的早期反应，是 HPSE 的重要来源。HPSE 似乎在巨噬细胞介导的肝星状细胞（HSCs）激活中起关键作用，因此表明 HPSE 靶向可能是治疗肝纤维化的新治疗选择。
