Department of Pharmacology and Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt; Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt.
Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt.
Int Immunopharmacol. 2024 Dec 25;143(Pt 1):113254. doi: 10.1016/j.intimp.2024.113254. Epub 2024 Sep 30.
Hepatopulmonary syndrome (HPS) is a liver disease-induced pulmonary complication manifested with arterial hypoxemia. Hepatic cholestasis, encountered in several clinical situations, leads to biliary cirrhosis and HPS, both of which are best reproduced by rat common bile duct ligation (CBDL). Experience from liver transplantation suggests hepatoprotective-based therapy would be most effective in HPS treatment Dipeptidyl peptidase-4 (DPP-4) enzyme is involved in different pathogenic mechanisms of liver diseases. Vildagliptin (Vild) is a DPP-4 inhibitor which possesses favorable anti-inflammatory, anti-oxidant and anti-fibrotic effects. The present work explored hepatoprotective mechanisms of Vild and their participation in its prophylactic effectiveness in HPS induced by CBDL in rats. Male Wistar rats weighing 220-280 g were allocated into 4 groups: normal control, sham, CBDL and CBDL + Vild groups. i.p. saline was administered to the first 3 groups and i.p. Vild (10 mg/kg/day) was given to the fourth group for 6 weeks starting 2 week before CBDL. CBDL produced liver fibrosis, arterial hypoxemia and decreased survivability of rats. It altered liver functions and induced oxidative stress, pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)], vasodilatory molecules [endothelin-1 (ET-1), and inducible and endothelial nitric oxide synthases] and angiogenesis-associated protein [vascular endothelial growth factor-A (VEGF-A)] in liver and lung. Vild ameliorated liver fibrosis, and improved hypoxemia and survivability of CBDL rats and reversed these biochemical alterations. Prophylactic Vild administration attenuated CBDL-induced HPS in rats via direct hepatoprotective effects in the form of anti-oxidant, anti-inflammatory, anti-angiogenic and anti-fibrotic effects beside inhibition of pathological intrahepatic vasodilatation.
肝肺综合征（HPS）是一种由肝脏疾病引起的肺部并发症，表现为动脉低氧血症。在几种临床情况下都会出现肝内胆汁淤积，导致胆汁性肝硬化和 HPS，而这两种情况都可以通过大鼠胆总管结扎（CBDL）来最好地重现。肝移植的经验表明，基于肝保护的治疗方法在 HPS 治疗中最有效。二肽基肽酶-4（DPP-4）酶参与肝脏疾病的不同发病机制。维格列汀（Vild）是一种 DPP-4 抑制剂，具有良好的抗炎、抗氧化和抗纤维化作用。本研究探讨了 Vild 的肝保护机制及其在预防 CBDL 诱导的大鼠 HPS 中的作用。雄性 Wistar 大鼠体重 220-280 g，分为 4 组：正常对照组、假手术组、CBDL 组和 CBDL+Vild 组。前三组给予腹腔注射生理盐水，第四组在 CBDL 前 2 周开始给予腹腔注射 Vild（10 mg/kg/天），持续 6 周。CBDL 导致肝纤维化、动脉低氧血症和大鼠存活率降低。它改变了肝功能并诱导氧化应激、促炎细胞因子[肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）]、血管舒张分子[内皮素-1（ET-1）、诱导型和内皮型一氧化氮合酶]和血管生成相关蛋白[血管内皮生长因子-A（VEGF-A）]在肝脏和肺部。Vild 改善了 CBDL 大鼠的肝纤维化，改善了低氧血症和存活率，并逆转了这些生化改变。预防性给予 Vild 通过直接的抗氧化、抗炎、抗血管生成和抗纤维化作用以及抑制肝内病理性血管扩张，减轻了 CBDL 诱导的大鼠 HPS。
