Background & Aims-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.
Endothelin-1 (ET-1T he endothelium plays a central role in the regulation of vascular tone both under normal circumstances and in cirrhosis by releasing endotheliumderived vasodilators and vasoconstrictors in response to a variety of biochemical and physical stimuli. 1 Nitric oxide (NO) and endothelin-1 (ET-1) are two important endothelial mediators that modulate vascular tone. Endothelial NO production is catalyzed predominately by the endothelial form of nitric oxide synthase (eNOS) and under normal circumstances is constitutively expressed and activated by calcium entry into cells. 2 ET-1 is a 21 amino acid peptide formed from a precursor, big ET-1, through the action of an endothelin-converting enzyme and is produced in a number of cell types in addition to endothelial cells, including hepatic stellate cells and biliary epithelium. 3-6 ET-1 is classically recognized as a potent paracrine vasoconstrictor, and its action is mediated by two G protein coupled receptors. 7,8 The endothelin A (ET A ) receptor mainly exists in vascular smooth muscle cells and mediates contraction and vasoconstriction. 9 Two endothelin B (ET B ) receptor types have been found: one in endothelial cells that upregulates eNOS and NO and the other in smooth muscle cells that functions similar to the ET A receptor. 10,11 Increased circulating ET-1, in part derived from increased hepatic production and
Hepatopulmonary syndrome (HPS) is a serious vascular complication of liver disease that occurs in 5-32% of patients with cirrhosis. The presence of HPS markedly increases mortality. No effective medical therapies are currently available and liver transplantation is the only established treatment option for HPS. The definition and diagnosis of HPS are established by the presence of a triad of liver disease with intrapulmonary vascular dilation that causes abnormal arterial gas exchange. Experimental biliary cirrhosis induced by common bile duct ligation in the rat reproduces the pulmonary vascular and gas exchange abnormalities of human HPS and serves as a pertinent animal model. Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental HPS, and thus might underlie HPS in humans. Defining the mechanisms involved in the microvascular alterations of HPS has the potential to lead to effective medical therapies. This Review focuses on the current understanding of the pathogenesis, clinical features and management of HPS.
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.
Background & Aims Hepatopulmonary syndrome (HPS), classically attributed to intrapulmonary vascular dilatation, occurs in 15-30% of cirrhotics and causes hypoxemia and increased mortality. In experimental HPS after common bile duct ligation (CBDL), monocytes adhere in the lung vasculature and produce vascular endothelial growth factor (VEGF)-A and angiogenesis ensues and contributes to abnormal gas exchange. However, the mechanisms for these events are unknown. The chemokine fractalkine (CX3CL1) can directly mediate monocyte adhesion and activate VEGF-A and angiogenesis via its receptor CX3CR1 on monocytes and endothelium during inflammatory angiogenesis. We explored whether pulmonary CX3CL1/CX3CR1 alterations occur after CBDL and influence pulmonary angiogenesis and HPS. Methods Pulmonary CX3CL1/CX3CR1 expression and localization, CX3CL1 signaling pathway activation, monocyte accumulation, and the development of angiogenesis and HPS were assessed in 2 and 4wk CBDL animals. The effects of a neutralizing antibody to CX3CR1 (anti-CX3CR1 Ab) on HPS after CBDL were evaluated. Results Circulating CX3CL1 levels and lung expression of CX3CL1 and CX3CR1 in intravascular monocytes and microvascular endothelium increased in 2 and 4wk CBDL animals as HPS developed. These events were accompanied by pulmonary angiogenesis, monocyte accumulation, activation of CX3CL1 mediated signaling pathways (Akt, ERK) and increased VEGF-A expression and signaling. Anti-CX3CR1 Ab treatment reduced monocyte accumulation, decreased lung angiogenesis and improved HPS. These events were accompanied by inhibition of CX3CL1 signaling pathways and a reduction in VEGF-A expression and signaling. Conclusions Circulating CX3CL1 levels and pulmonary CX3CL1/CX3CR1 expression and signaling increase after CBDL and contribute to pulmonary intravascular monocyte accumulation, angiogenesis and the development of experimental HPS.
MB. Pentoxifylline attenuation of experimental hepatopulmonary syndrome. J Appl Physiol 102: 949 -955, 2007. First published November 16, 2006; doi:10.1152/japplphysiol.01048.2006.-Hepatopulmonary syndrome (HPS) following rat common bile duct ligation results from pulmonary molecular changes that may be influenced by circulating TNF-␣ and increased vascular shear stress, through activation of NF-B or Akt. Increased pulmonary microvascular endothelin B (ETB) receptor and endothelial nitric oxide synthase (eNOS) levels contribute to nitric oxide production and the development of experimental HPS. Pentoxifylline (PTX), a phosphodiesterase and nonspecific TNF-␣ inhibitor, ameliorates experimental HPS when begun before hepatic injury. However, how PTX influences the molecular events associated with initiation of experimental HPS after liver injury is established is unknown. We assessed the effects of PTX on the molecular and physiological features of HPS in vivo and on shear stress or TNF-␣-mediated events in rat pulmonary microvascular endothelial cells in vitro. PTX significantly improved HPS without altering portal or systemic hemodynamics and downregulated pulmonary ETB receptor levels and eNOS expression and activation. These changes were associated with a reduction in circulating TNF levels and NF-B activation and complete inhibition of Akt activation. In rat pulmonary microvascular endothelial cells, PTX inhibited shear stress-induced ETB receptor and eNOS expression and eNOS activation. These effects were also associated with inhibition of Akt activation and were reproduced by wortmanin. In contrast, TNF-␣ had no effects on endothelial ETB and eNOS alterations in vitro. PTX has direct effects in the pulmonary microvasculature, likely mediated through Akt inhibition, that ameliorate experimental HPS. common bile duct ligation; endothelial cells; endothelin B receptor; endothelial nitric oxide synthase THE HEPATOPULMONARY SYNDROME (HPS) results when intrapulmonary vascular dilatation causes hypoxemia in the setting of liver disease or portal hypertension (13). This syndrome is found in 10 -20% of patients with cirrhosis, and its presence increases mortality (15). Despite a significant increase in our understanding of HPS over the last 20 years, its pathogenesis remains incompletely understood, and no medical therapies are available.Chronic common bile duct ligation (CBDL) in the rat leading to biliary cirrhosis reproduces the pulmonary physiological abnormalities of human HPS and serves as an experimental model (2). A series of alterations in the pulmonary microvasculature, including endothelin-1 (ET-1)-mediated endothelial nitric oxide (NO) synthase (eNOS) activation and NO production via increased endothelial endothelin B (ET B ) receptors (8 -10, 19), and accumulation and activation of intravascular macrophages, leading to inducible NO synthase (iNOS)-derived NO production and heme oxygenase (HO)-1-derived carbon monoxide production (12, 17, 18), have been identified after CBDL and contribute to intrapulmona...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.