Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver
Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver
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DOI：
10.1152/ajpgi.00037.2003
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发表时间：
2003-09-01
影响因子：
4.5
通讯作者：
Rippe, RA
中科院分区：
文献类型：
--
作者：
Bataller, R;Gäbele, E;Rippe, RA
最近的证据表明血管紧张素 II (ANG II) 在肝纤维形成中发挥重要作用。然而，其根本机制在很大程度上尚不清楚。在晚期慢性肝病中，ANG II 的循环水平经常升高。我们研究了长期全身输注 ANG II 对正常大鼠的肝脏影响。通过皮下渗透泵向正常大鼠输注亚加压剂量和加压剂量（分别为15和50 ng.kg(-1).min(-1)）的生理盐水或ANG II，持续4周。根据血清肝酶升高的评估，ANG II 输注会导致肝损伤。 ANG II 灌注大鼠的肝脏显示出 JNK 和 ERK 的激活以及 NF-kappaB 和激活 Protein-1 DNA 结合活性的增加。此外，ANG II灌注可诱导氧化应激，增加促炎细胞因子的浓度，并上调炎症蛋白诱导型一氧化氮合酶和环氧合酶-2。 ANG II 输注大鼠的肝脏组织学检查显示轻度门静脉炎症以及小肝血管增厚和血栓形成。 ANG II 处理的肝脏显示 CD43 阳性炎症细胞和活化的肝星状细胞 (HSC) 在中央周围区域积聚。通过天狼星红染色和肝羟脯氨酸评估，观察到胶原蛋白合成略有增加。当以亚升压和升压剂量灌注 ANG II 时，观察到所有这些效应。 ANG II 还加速了原代培养的大鼠 HSC 的激活。总之，全身性 ANG II 增加可通过促进促炎事件和血管损伤而诱发肝损伤。 ANG II 引起的肝脏影响不依赖于动脉压的增加。
Recent evidence indicates that angiotensin II (ANG II) plays an important role in liver fibrogenesis. However, the underlying mechanisms are largely unknown. In advanced chronic liver diseases, circulating levels of ANG II are frequently elevated. We investigated the hepatic effects of prolonged systemic infusion of ANG II in normal rats. Saline or ANG II at subpressor and pressor doses (15 and 50 ng.kg(-1).min(-1), respectively) were infused to normal rats for 4 wk through a subcutaneous osmotic pump. Infusion of ANG II resulted in liver injury, as assessed by elevated serum liver enzymes. Livers from ANG II-perfused rats showed activation of JNK and ERK as well as increased NF-kappaB and activating protein-1 DNA-binding activity. Moreover, ANG II perfusion induced oxidative stress, increased concentration of proinflammatory cytokines, and upregulated the inflammatory proteins inducible nitric oxide synthase and cyclooxygenase-2. Histological examination of the livers from ANG II-infused rats showed mild portal inflammation as well as thickening and thrombosis of small hepatic vessels. ANG II-treated livers showed accumulation of CD43-positive inflammatory cells and activated hepatic stellate cells (HSCs) at the pericentral areas. A slight increase in collagen synthesis was observed, as assessed by Sirius red staining and hepatic hydroxyproline. All of these effects were observed when ANG II was perfused at subpressor and pressor doses. ANG II also accelerated the activation of primary cultured rat HSCs. In conclusion, increased systemic ANG II can induce liver injury by promoting proinflammatory events and vascular damage. ANG II-induced hepatic effects are not dependent on increase in arterial pressure.