Metformin reduces intrahepatic fibrosis and intrapulmonary shunts in biliary cirrhotic rats

Abstract

BackgroundLiver fibrosis causes portal hypertension which dilates collateral vasculature and enhances extra-hepatic angiogenesis including intrapulmonary shunts, which subsequently complicates with hepatopulmonary syndrome. Metformin is an anti-diabetic agent which possesses anti-inflammation and anti-angiogenesis properties. This study evaluated the effect of metformin treatment on liver and lung in a non-diabetic rat model with biliary cirrhosis induced via common bile duct ligation (CBDL). MethodsCBDL rats were fed with metformin 150 mg/kg/day during the 8th–28th day post operation. The hemodynamic and biochemistry parameters were tested, and blood gas analysis was performed. The liver and lung were dissected for protein analysis and immuno-histochemical stains. Intrapulmonary shunting degree was determined using color microsphere method. ResultsMetformin treatment neither induced obvious hypoglycemic event nor altered hemodynamics in cirrhotic rats. The plasma levels of alanine aminotransferase were significantly reduced by metformin (control vs. metformin: 269 ± 56 vs. 199 ± 21 IU/L, P = 0.02). Sirius Red stains and CD-68 stains showed that metformin reduced intrahepatic fibrosis and CD-68-positive macrophages. Metformin did not influence hypoxia and intrapulmonary angiogenesis; however, it significantly reduced intrapulmonary shunts (31.7 ± 10.1 vs. 15.0 ± 6.6%, P = 0.006.). Furthermore, metformin reduced the protein expressions of COX-2 and PI3K in liver and COX-1 in lung. ConclusionMetformin reduced liver injury and improved hepatic fibrosis in cirrhotic rats. It also attenuated the intrapulmonary shunts. However, the effects of metformin on pulmonary angiogenesis and hypoxia were insignificant.