Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.
J Chin Med Assoc. 2017 Aug;80(8):467-475. doi: 10.1016/j.jcma.2017.05.005. Epub 2017 Jul 1.
Liver 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).
CBDL 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.
Metformin 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.
Metformin 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.
肝纤维化导致门静脉高压，从而扩张侧支血管并增强肝外血管生成，包括肺内分流，随后合并肝肺综合征。二甲双胍是一种抗糖尿病药物，具有抗炎和抗血管生成的特性。本研究评估了二甲双胍治疗在通过胆总管结扎（CBDL）诱导的非糖尿病大鼠胆汁性肝硬化模型中的肝和肺的作用。
CBDL 大鼠在术后第 8-28 天每天给予二甲双胍 150mg/kg。测试血流动力学和生化参数，并进行血气分析。分离肝和肺进行蛋白质分析和免疫组织化学染色。使用彩色微球法确定肺内分流程度。
二甲双胍治疗既没有在肝硬化大鼠中引起明显的低血糖事件，也没有改变血流动力学。二甲双胍显著降低了血浆丙氨酸氨基转移酶水平（对照组与二甲双胍组：269±56 vs. 199±21IU/L，P=0.02）。天狼星红染色和 CD-68 染色显示，二甲双胍减少了肝内纤维化和 CD-68 阳性巨噬细胞。二甲双胍不影响缺氧和肺内血管生成，但显著减少了肺内分流（31.7±10.1 vs. 15.0±6.6%，P=0.006）。此外，二甲双胍降低了肝和 COX-1 中的 COX-2 和 PI3K 蛋白表达。
二甲双胍减轻了肝硬化大鼠的肝损伤和肝纤维化，减少了肺内分流。然而，二甲双胍对肺血管生成和缺氧的影响不显著。
