Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Al Azhar University, Assiut, 71524, Egypt.
Eur J Pharmacol. 2020 Apr 15;873:173008. doi: 10.1016/j.ejphar.2020.173008. Epub 2020 Feb 9.
Hepatopulmonary syndrome (HPS) is a severe complication of hepatic cirrhosis, which is characterized by hypoxia, intrapulmonary vasodilation, inflammation, and angiogenesis. In this study, we aimed to investigate the regulatory effects of diosmin (DS) on selected phosphodiesterase inhibitors against chronic bile duct ligation (CBDL)-induced HPS. Experimentally, Wistar Albino rats were used and HPS was induced by CBDL for 28 days. DS (100 mg/kg, daily, P.O.), sildenafil (Sild; 10 mg/kg, twice daily, P.O.), and pentoxifylline (PTX; 50 mg/kg, daily, P.O.) were evaluated either alone or in combinations for their anti-angiogenic activity. CBDL significantly altered oxidative stress biomarkers and up-regulated pulmonary mRNA expressions of VEGF, IGF-1, ET-1, iNOS, eNOS, and ANG-2 as well as the protein expressions of vWF, FGF-1, PI3K, AKT, p-AKT, TGF-β, HYP, MPO activity and circulating TNF-α. Treatment with DS, Sild, PTX, and their combinations significantly attenuated molecular and cellular changes due to CBDL. Improvement of histopathological changes was also observed after drug treatment which further supported our results. Furthermore, DS combination with Sild or PTX exhibited an improvement in HPS in comparison to each drug alone. Collectively, DS can augment the anti-angiogenic activity of Sild and PTX during HPS through regulation of TNF-α/VEGF, IGF-1/PI3K/AKT, and FGF-1/ANG-2 signaling pathways.
肝肺综合征（HPS）是肝硬化的一种严重并发症，其特征为缺氧、肺内血管扩张、炎症和血管生成。在本研究中，我们旨在研究地奥司明（DS）对选定的磷酸二酯酶抑制剂在慢性胆管结扎（CBDL）诱导的 HPS 中的调节作用。实验中，使用 Wistar 白化大鼠，并通过 CBDL 诱导 28 天来诱导 HPS。DS（100mg/kg，每日，PO）、西地那非（Sild；10mg/kg，每日两次，PO）和己酮可可碱（PTX；50mg/kg，每日，PO）单独或联合评估其抗血管生成活性。CBDL 显著改变了氧化应激生物标志物，并上调了肺 VEGF、IGF-1、ET-1、iNOS、eNOS 和 ANG-2 的 mRNA 表达以及 vWF、FGF-1、PI3K、AKT、p-AKT、TGF-β、HYP、MPO 活性和循环 TNF-α 的蛋白表达。DS、Sild、PTX 及其组合治疗可显著减轻由于 CBDL 引起的分子和细胞变化。药物治疗后还观察到组织病理学变化的改善，这进一步支持了我们的结果。此外，与每种药物单独使用相比，DS 与 Sild 或 PTX 的联合使用可改善 HPS。总之，DS 可以通过调节 TNF-α/VEGF、IGF-1/PI3K/AKT 和 FGF-1/ANG-2 信号通路增强 Sild 和 PTX 在 HPS 中的抗血管生成活性。
