Hepatoprotective effects of vildagliptin mitigates lung biochemical and histopathological changes in experimental hepatopulmonary syndrome model in rat

• Published in: International immunopharmacology 2024-12, Vol.143 (Pt 1), p.113254, Article 113254
• Main Authors: Mangoura, Safwat A., Ahmed, Marwa A., Hamad, Nashwa, Zaka, Andrew Z., Khalaf, Khaled A.
• Format: Article
• Language: English
• Subjects: Common bile duct ligation; Dipeptidyl peptidase-4; Hepatoprotective; Hepatopulmonary syndrome; Pleiotropic actions; Vildagliptin
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.113254

•Hepatopulmonary syndrome, manifested by arterial hypoxemia, is frequently encountered in several hepatic diseases as hepatic cholestasis; both conditions are best reproduced by rat common bile duct ligation.•Experience from liver transplantation suggests that hepatoprotective-based therapy would be most effective in HPS treatment. Hence, targeting dipeptidyl peptidase-4 (DPP-4) enzyme, which is involved in different pathogenic mechanisms of liver diseases, may offer promising therapeutic tool in HPS management.•Vildagliptin 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.•Prophylactic vildagliptin administration ameliorated liver fibrosis, and improved hypoxemia and survivability of CBDL 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. 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