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

Authors

  • Lichuan Liu,

    1. From the Department of Internal Medicine, Liver Center, University of Alabama at Birmingham and the Birmingham Veterans Administration Medical Center, Birmingham, AL
    Search for more papers by this author
  • Ming Zhang,

    1. From the Department of Internal Medicine, Liver Center, University of Alabama at Birmingham and the Birmingham Veterans Administration Medical Center, Birmingham, AL
    Search for more papers by this author
  • Bao Luo,

    1. From the Department of Internal Medicine, Liver Center, University of Alabama at Birmingham and the Birmingham Veterans Administration Medical Center, Birmingham, AL
    Search for more papers by this author
  • Gary A. Abrams,

    1. From the Department of Internal Medicine, Liver Center, University of Alabama at Birmingham and the Birmingham Veterans Administration Medical Center, Birmingham, AL
    Search for more papers by this author
  • Michael B. Fallon M.D.

    Corresponding author
    1. From the Department of Internal Medicine, Liver Center, University of Alabama at Birmingham and the Birmingham Veterans Administration Medical Center, Birmingham, AL
    • University of Alabama at Birmingham, 410 LHRB, 701 South 19th St. Birmingham, AL 35294-0007. fax: 205-975-9393.
    Search for more papers by this author

Abstract

The hepatopulmonary syndrome (HPS) results from pulmonary microvascular dilatation in cirrhosis and is associated with increased pulmonary endothelial nitric oxide synthase (eNOS) levels. In the common bile duct ligation (CBDL) model, endothelin-1 (ET-1) released from the liver contributes to the rise in pulmonary eNOS and intrapulmonary vasodilatation. Whether substances, including ET-1, are found in the biliary tree and selectively enter the circulation after CBDL to influence the pulmonary vasculature is unknown. We assessed if control bile and fluid obtained from the obstructed biliary tree in CBDL animals contains ET-1 and alters eNOS expression and activity in bovine pulmonary artery endothelial cells (BPAECs). Control bile and biliary cyst fluid contained concentrations of ET-1 25- to 42-fold normal plasma levels, and hepatic venous concentrations of ET-1 were selectively increased 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 enzyme activity (2.2-fold control) maximal at a 1:10 dilution. The increases were associated with enhanced nitric oxide (NO) production (3.1-fold control) and were inhibitable with an ETB receptor antagonist. Bile from sham and portal vein–ligated animals did not increase eNOS expression and at dilutions of 1:100 and 1:10 caused cell toxicity. These results show that bile and biliary cyst fluid contain high concentrations of ET-1 that are specifically increased in hepatic venous blood after CBDL. Biliary cyst fluid increases eNOS expression and activity in an ETB receptor–dependent manner in BPAECs. The findings suggest a novel mechanism for the susceptibility of CBDL animals to the HPS.

Ancillary