吡格列酮对肝硬化合并肝肺综合征大鼠的作用。

The effects of pioglitazone in cirrhotic rats with hepatopulmonary syndrome.

机构信息

Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.

出版信息

J Chin Med Assoc. 2017 Nov;80(11):683-689. doi: 10.1016/j.jcma.2017.08.010. Epub 2017 Sep 29.

DOI:10.1016/j.jcma.2017.08.010

PMID:28969989

Abstract

BACKGROUND

Hepatopulmonary syndrome (HPS) is characterized by oxygen desaturation and increased intrapulmonary shunting formation in cirrhosis. Due to an unclarified mechanism, there is still no effective therapy except liver transplantation. Recent studies revealed that pulmonary angiogenesis may participate in pathogenesis, in which nitric oxide (NO) and vascular endothelial growth factor (VEGF) play roles. Pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, exerts anti-angiogenesis effect. However, whether pioglitazone influences pulmonary angiogenesis, shunting and HPS remains unexplored.

METHODS

Cirrhosis with HPS was induced in Spraque-Dawley rats with common bile duct ligation (CBDL). Pioglitazone (10 mg/kg/day, oral gavage) or vehicle was administered from 8th to 28th day post CBDL. On the 28th day, the mortality rate, hemodynamic parameters, concentrations of plasma glucose and liver biochemistry parameters, and arterial blood gas data were evaluated. Lungs were dissected for protein expression analyses. In another series, intrapulmonary shunting degree was determined by color microsphere method in paralleled groups.

RESULTS

The survival rates were similar in HPS rats with or without pioglitazone administration. Pioglitazone did not influence the hemodynamic parameters, glucose and liver biochemistry levels, oxygen saturation and alveolar arterial gradient, but significantly down-regulated pulmonary VEGF protein expression, endothelial NO synthase (eNOS) activation, and decreased intrapulmonary shunts. Pioglitazone significantly decreased intrapulmonary shunts as compared with the vehicle (18.1 ± 4.5 vs. 9.8 ± 3.6, p = 0.015).

CONCLUSION

Pioglitazone down-regulated VEGF, eNOS and decreased intrapulmonary shunts without improving oxygenation. The current finding suggests a multifactorial mechanism of HPS that could not be successfully overcome merely by pioglitazone-induced anti-angiogenesis and shunting reduction.

摘要

背景

肝肺综合征（HPS）的特征是肝硬化患者发生氧合作用下降和肺内分流形成增加。由于机制尚未阐明，除肝移植外，目前尚无有效的治疗方法。最近的研究表明，肺血管生成可能参与发病机制，其中一氧化氮（NO）和血管内皮生长因子（VEGF）起作用。吡格列酮是一种过氧化物酶体增殖物激活受体γ激动剂，具有抗血管生成作用。然而，吡格列酮是否影响肺血管生成、分流和 HPS 尚不清楚。

方法

采用胆总管结扎（CBDL）诱导 Spraque-Dawley 大鼠发生 HPS 型肝硬化。从 CBDL 后第 8 天至第 28 天，给予吡格列酮（10mg/kg/天，口服灌胃）或载体。第 28 天，评估死亡率、血流动力学参数、血浆葡萄糖和肝功能参数浓度以及动脉血气数据。分离肺部进行蛋白表达分析。在另一系列中，通过彩色微球法平行组确定肺内分流程度。

结果

HPS 大鼠无论是否给予吡格列酮，其存活率均相似。吡格列酮不影响血流动力学参数、血糖和肝功能水平、氧饱和度和肺泡动脉梯度，但显著下调肺 VEGF 蛋白表达、内皮型一氧化氮合酶（eNOS）激活，并减少肺内分流。与载体相比，吡格列酮显著降低肺内分流（18.1±4.5 对 9.8±3.6，p=0.015）。