thioacetamide and Hepatopulmonary-Syndrome

About eighteen percent of cirrhotic patients come along with decreased systemic arterial oxygenation and expansion of pulmonary venous plexus which triggered by nitric oxide. The level of nitrate and iNOS significantly increase in the cirrhotic patients. However the localization of nNOS and iNOS in the lung tissue has not yet been clarified.. The present study, therefore, aimed to demonstrate the sites of expansion of pulmonary blood vessels and to localize nNOS and iNOS in the lung tissue of cirrhotic rat models induced by thioacetamide (TAA).. The rats were divided into 5 groups. The first group was the control. The other four groups were treated with 200 mg/kg body weight of TAA 3 times per week for 1, 2, 3, or 4 month(s), respectively. At the end of each month rats in each treated group were sacrificed. Lung histology and pulmonary NOS expression was studied by light microscope and immunohistochemical technique, respectively.. It was found that diameter of blood vessels were highest increased in the right lower lobe of the 4-months TAA-treated group. In addition, iNOS and nNOS expression was localized at epithelium of respiratory tract, endothelium of pulmonary vessel and macrophage at this age.. The present study demonstrated that the pulmonary blood vessels at the right lower lobe with cirrhotic background got enormous dilatation. iNOS and nNOS were immunostained at epithelium of respiratory tract, pulmonary endothelium and macrophages. Our observations suggested that enhanced NOS expression is important in the development of systemic hyperdynamic circulatory abnormalities in cirrhosis. As appearance of vasodilatation at right lower lobe of lung, it could, therefore, be evidence confirming that there was a real connection between inferior pulmonary vein and azygos vein at the embryonic period but obliterated later.

Topics: Analysis of Variance; Animals; Case-Control Studies; Hepatopulmonary Syndrome; Immunohistochemistry; Liver Cirrhosis, Experimental; Male; Nitric Oxide Synthase; Rats; Rats, Wistar; Thioacetamide; Vasodilation

Hepatopulmonary syndrome (HPS), defined as intrapulmonary vasodilation, occurs in 10%-30% of cirrhotics and increases mortality. In a rat model of HPS induced by common bile duct ligation (CBDL), but not thioacetamide (TAA)-induced nonbiliary cirrhosis, lung capillary density increases, monocytes accumulate in the microvasculature, and signaling factors in the angiogenesis pathway (Akt and endothelial nitric oxide synthase [eNOS]) are activated. Pentoxifylline (PTX) directly decreases lung endothelial Akt and eNOS activation, blocks intravascular monocyte accumulation, and improves experimental HPS; we evaluated whether pulmonary angiogenesis develops in this model.. TAA- and PTX-treated animals were evaluated following CBDL. Lung angiogenesis was assessed by quantifying factor VIII-positive microvessels and levels of von Willebrand factor (vWf), vascular endothelial cadherin (VE-cadherin), and proliferating cell nuclear antigen (PCNA). Angiogenic factors including phospho-Akt, phospho-eNOS, vascular endothelial growth factor (VEGF)-A, and phospho-VEGF receptor-2 (p-VEGFR-2) were compared and monocyte accumulation was assessed.. Following CBDL, but not TAA exposure, rats developed HPS that was temporally correlated with increased numbers of lung microvessel; increased levels of vWf, VE-cadherin and PCNA; and activation of Akt and eNOS. Angiogenesis was accompanied by increased pulmonary VEGF-A and p-VEGFR-2 levels, with VEGF-A staining in accumulated intravascular monocytes and alveolar endothelial cells. Following CBDL, PTX-treated rats had reduced numbers of microvessels, reduced lung monocyte accumulation, downregulation of pulmonary angiogenic factors, and reduced symptoms of HPS.. A specific increase in pulmonary angiogenesis occurs as experimental HPS develops, accompanied by activation of VEGF-A-associated angiogenic pathways. PTX decreases the angiogenesis, reduces the symptoms of HPS, and downregulates VEGF-A mediated pathways.

Topics: Angiostatins; Animals; Common Bile Duct; Disease Models, Animal; Endostatins; Hepatopulmonary Syndrome; Ligation; Male; Microcirculation; Neovascularization, Pathologic; Nitric Oxide Synthase Type III; Pentoxifylline; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-akt; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Signal Transduction; Thioacetamide; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vasodilator Agents

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.

Topics: Animals; Endothelin-1; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hepatopulmonary Syndrome; Hypertension, Portal; Ligation; Liver Cirrhosis; Liver Cirrhosis, Biliary; Lung; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Portal Vein; Rats; Rats, Sprague-Dawley; Thioacetamide; Tumor Necrosis Factor-alpha