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LIVER AND BILIARY TRACT

ET-1 and TNF- in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats

¹Department of Internal Medicine and Liver Center, University of Alabama at Birmingham, and ²Birmingham Veterans Administration Medical Center, Birmingham, Alabama, 35294

Submitted 16 July 2003 ; accepted in final form 11 September 2003

Common bile duct ligation (CBDL) triggers a molecular cascade resulting in the hepatopulmonary syndrome (HPS). Both increased hepatic endothelin-1 (ET-1) production and pulmonary vascular ET_B receptor expression with stimulation of endothelial nitric oxide synthase and TNF- mediated inducible nitric oxide synthase and heme oxygenase-1 expression in pulmonary intravascular macrophages occur. Whether biliary cirrhosis is unique in triggering ET-1 and TNF- alterations and HPS is unknown. We evaluated for HPS in rat prehepatic portal hypertension [partial portal vein ligation (PVL)], biliary (CBDL) and nonbiliary [thioacetamide treatment (TAA)] cirrhosis, and assessed ET-1 infusion in normal and PVL animals. Control, PVL, CBDL, TAA-treated, and ET-1-infused PVL animals had ET-1 and TNF- levels measured and underwent molecular and physiological evaluation for HPS. HPS developed only in biliary cirrhosis in association with increased plasma ET-1 and TNF- levels and the development of established molecular changes in the pulmonary microvasculature. In contrast, PVL did not increase ET-1 or TNF- levels and TAA treatment increased TNF- levels alone, and neither resulted in the full development of molecular or physiological changes of HPS despite portal pressure increases similar to those after CBDL. Exogenous ET-1 increased TNF- levels and triggered HPS after PVL. Combination of ET-1 and TNF- overproduction is unique to biliary cirrhosis and associated with experimental HPS. ET-1 infusion increases TNF- levels and triggers HPS in prehepatic portal hypertension. ET-1 and TNF- interact to trigger pulmonary microvascular changes in experimental HPS.

partial portal vein ligation; common bile duct ligation; thioacetamide; nitric oxide synthase; endothelin B receptor

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