title: ET-1 and TNF-alpha in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats.
abstract: 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-alpha 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-alpha 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-alpha 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-alpha levels and the development of established molecular changes in the pulmonary microvasculature. In contrast, PVL did not increase ET-1 or TNF-alpha levels and TAA treatment increased TNF-alpha 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-alpha levels and triggered HPS after PVL. Combination of ET-1 and TNF-alpha overproduction is unique to biliary cirrhosis and associated with experimental HPS. ET-1 infusion increases TNF-alpha levels and triggers HPS in prehepatic portal hypertension. ET-1 and TNF-alpha interact to trigger pulmonary microvascular changes in experimental HPS.
authors.affiliation: Department of Internal Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.
authors.forename: Bao
authors.initials: B
authors.lastname: Luo
authors.forename: Lichuan
authors.initials: L
authors.lastname: Liu
authors.forename: Liping
authors.initials: L
authors.lastname: Tang
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhang
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Ling
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fallon
mesh_terms: D000818:Animals; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D020065:Hepatopulmonary Syndrome / Q000378:metabolism*; D006975:Hypertension, Portal / Q000209:etiology / Q000378:metabolism; D008026:Ligation; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011169:Portal Vein; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D014409:Tumor Necrosis Factor-alpha; D013853:Thioacetamide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1