Biliary cyst fluid from common bile duct-ligated rats stimulates endothelial nitric oxide synthase in pulmonary artery endothelial cells: A potentialrole in hepatopulmonary syndrome

The hepatopulmonary syndrome (HPS) results from pulmonary microvascular dil atation in cirrhosis and is associated with increased pulmonary endothelial nitric oxide synthase (eNOS) levels. In the common bile duct ligation (CBD L) model, endothelin-1 (ET-1) released from the liver contributes to the ri se in pulmonary eNOS and intrapulmonary vasodilatation. Whether substances, including ET-1, are found in the biliary tree and selectively enter the ci rculation after CBDL to influence the pulmonary vasculature is unknown. We assessed if control bile and fluid obtained from the obstructed biliary tre e in CBDL animals contains ET-1 and alters eNOS expression and activity in bovine pulmonary artery endothelial cells (BPAECs). Control bile and biliar y cyst fluid contained concentrations of ET-1 25- to 42-fold normal plasma levels, and hepatic venous concentrations of ET-1 were selectively increase d after CBDL. Biliary cyst fluid caused a dose-dependent induction of eNOS messenger RNA (mRNA) (1.9-fold control), protein (2.5-fold control), and en zyme activity (2.2-fold control) maximal at a 1:10 dilution. The increases were associated with enhanced nitric oxide (NO) production (3.1-fold contro l) and were inhibitable with an ETB receptor antagonist. Bile from sham and portal vein-ligated animals did not increase eNOS expression and at diluti ons of 1:100 and 1:10 caused cell toxicity. These results show that bile an d biliary cyst fluid contain high concentrations of ET-1 that are specifica lly increased in hepatic venous blood after CBDL, Biliary cyst fluid increa ses eNOS expression and activity in an ETB receptor-dependent manner in BPA ECs. The findings suggest a novel mechanism for the susceptibility of CBDL animals to the HPS.