J Pharmacol Exp Ther. 2018 Sep 7. pii: jpet.118.250431. doi: 10.1124/jpet.118.250431. [Epub ahead of print]
Nucleos(t)ide analogs do not independently influence hepatic fibrosis and portal hypertension beyond viral suppression in CBDL-induced cirrhotic rat.
Hsieh YH1, Huang HC1, Chang CC1, Chuang CL1, Lee FY1, Hsu SJ2, Huang YH1, Hou MC1, Lee SD1.
Author information
1
Taipei veteran general hospital.
2
Taipei veteran general hospital [email protected].
Abstract
Chronic hepatitis is the major cause of liver cirrhosis and portal hypertension. Several factors affect portal pressure, including liver fibrosis, splanchnic vasodilatation and pathological angiogenesis. Nucleos(t)ide analogs (NUCs), the oral antiviral agents, effectively attenuate chronic hepatitis B-related liver cirrhosis and portal hypertension via viral suppression and alleviation of hepatitis. On the other hand, NUCs affect TNF-α, vascular endothelial growth factor (VEGF) and nitric oxide, which participate in fibrogenesis, vasodilatation and angiogenesis. However, whether NUCs independently influence liver fibrosis and portal hypertension beyond viral suppression is unknown. This study thus aimed to evaluate the influences of three frequently used NUCs in rats with non-viral cirrhosis. Male Sprague-Dawley rats received common bile duct ligation (CBDL) to induce cholestatic cirrhosis and portal hypertension. The rats were randomly allocated into four groups, treated per oral with lamivudine (30 mg/kg/day), entecavir (0.09 mg/kg/day), tenofovir (50 mg/kg/day) or distilled water (vehicle control) since the 15th day after CBDL. On the 29th day, liver cirrhosis and portal hypertension-related parameters were evaluated. The results showed that chronic NUCs treatment did not affect hemodynamic parameters, plasma TNF-α concentration, and hepatic fibrogenesis protein expressions in rats with non-viral cirrhosis. Though the mesenteric VEGF receptor 2 phosphorylation was down-regulated in NUCs-treated groups, the splanchnic angiogenesis was not influenced. In conclusion, lamivudine, entecavir and tenofovir had no additional effects on liver cirrhosis and portal hypertension in rats with non-viral cirrhosis.
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慢性肝炎是肝硬化和门静脉高压的主要原因。几个因素影响门静脉压力，包括肝纤维化，内脏血管舒张和病理性血管生成。核酸类似物（NUCs）是口服抗病毒药物，通过病毒抑制和减轻肝炎，有效减轻慢性乙型肝炎相关性肝硬化和门静脉高压症。另一方面，NUC影响TNF-α，血管内皮生长因子（VEGF）和一氧化氮，它们参与纤维发生，血管舒张和血管生成。然而，NUC是否独立影响肝纤维化和门静脉高压超出病毒抑制是未知的。因此，该研究旨在评估三种常用NUC在非病毒性肝硬化大鼠中的影响。雄性Sprague-Dawley大鼠接受胆总管结扎（CBDL）以诱导胆汁淤积性肝硬化和门静脉高压症。将大鼠随机分为4组，每次口服拉米夫定（30mg / kg /天），恩替卡韦（0.09mg / kg /天），替诺福韦（50mg / kg /天）或蒸馏水（载体对照）。 CBDL之后的第15天。在第29天，评估肝硬化和门静脉高压相关参数。结果显示，慢性NUCs治疗不影响非病毒性肝硬化大鼠的血流动力学参数，血浆TNF-α浓度和肝纤维化蛋白表达。尽管在NUCs治疗组中肠系膜VEGF受体2磷酸化被下调，但内脏血管生成未受影响。总之，拉米夫定，恩替卡韦和替诺福韦对非病毒性肝硬化大鼠的肝硬化和门静脉高压没有额外的影响。
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