The effects of pioglitazone in cirrhotic rats with hepatopulmonary syndrome

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.