The role of endothelial nitric oxide synthase in the pathogenesis of a rat model of hepatopulmonary syndrome
Abstract
BACKGROUND & AIMS: The hepatopulmonary syndrome occurs when intrapulmonary vasodilatation causes impaired arterial gas exchange in liver disease. The pathogenesis is poorly understood, although nitric oxide may be involved. Common bile duct ligation in the rat is a model of the hepatopulmonary syndrome, but no studies have evaluated NO in pulmonary vasodilatation in this model. The aim of this study was to determine whether NO contributes to intrapulmonary vasodilatation after bile duct ligation.
METHODS: Endothelial and inducible NO synthase (NOS) levels and localization and NO activity in pulmonary artery rings were assessed after bile duct ligation.
RESULTS: Pulmonary endothelial NOS levels increased and alveolar vascular staining was enhanced after bile duct ligation. No change in pulmonary inducible NOS levels or localization was detected. Increased endothelial NOS levels correlated with alterations in gas exchange and were accompanied by enhanced NO activity and a blunted response to phenylephrine, reversible by NOS inhibition, in pulmonary artery rings. Portal-vein-ligated animals, which do not develop intrapulmonary vasodilatation, had no changes in pulmonary NOS production or in NO activity in pulmonary artery rings.
CONCLUSIONS: NO, derived from pulmonary vascular endothelial NOS, contributes to intrapulmonary vasodilation in animal hepatopulmonary syndrome.
(Gastroenterology 1997 Aug;113(2):606-14)
References (0)
Cited by (213)
Hepatopulmonary syndrome is associated with low sphingosine-1-phosphate levels and can be ameliorated by the functional agonist fingolimod
2023, Journal of HepatologyHepatopulmonary syndrome (HPS) is characterised by a defect in arterial oxygenation induced by pulmonary vascular dilatation in patients with liver disease. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, suppresses vasodilation by reducing nitric oxide (NO) production. We investigated the role of S1P in patients with HPS and the role of fingolimod as a therapeutic option in an experimental model of HPS.
Patients with cirrhosis with HPS (n = 44) and without HPS (n = 89) and 25 healthy controls were studied. Plasma levels of S1P, NO, and markers of systemic inflammation were studied. In a murine model of common bile duct ligation (CBDL), variations in pulmonary vasculature, arterial oxygenation, liver fibrosis, and inflammation were estimated before and after administration of S1P and fingolimod.
Log of plasma S1P levels was significantly lower in patients with HPS than in those without HPS (3.1 ± 1.4 vs. 4.6 ± 0.2; p <0.001) and more so in severe intrapulmonary shunting than in mild and moderate intrapulmonary shunting (p <0.001). Plasma tumour necrosis factor-α (76.5 [30.3–91.6] vs. 52.9 [25.2–82.8]; p = 0.02) and NO (152.9 ± 41.2 vs. 79.2 ± 29.2; p = 0.001) levels were higher in patients with HPS than in those without HPS. An increase in Th17 (p <0.001) and T regulatory cells (p <0.001) was observed; the latter inversely correlated with plasma S1P levels. In the CBDL HPS model, fingolimod restored pulmonary vascular injury by increasing the arterial blood gas exchange and reducing systemic and pulmonary inflammation, resulting in improved survival (p = 0.02). Compared with vehicle treatment, fingolimod reduced portal pressure (p <0.05) and hepatic fibrosis and improved hepatocyte proliferation. It also induced apoptotic death in hepatic stellate cells and reduced collagen formation.
Plasma S1P levels are low in patients with HPS and even more so in severe cases. Fingolimod, by improving pulmonary vascular tone and oxygenation, improves survival in a murine CBDL HPS model.
A low level of plasma sphingosine-1-phosphate (S1P) is associated with severe pulmonary vascular shunting, and hence, it can serve as a marker of disease severity in patients with hepatopulmonary syndrome (HPS). Fingolimod, a functional agonist of S1P, reduces hepatic inflammation, improves vascular tone, and thus retards the progression of fibrosis in a preclinical animal model of HPS. Fingolimod is being proposed as a potential novel therapy for management of patients with HPS.
Hepatopulmonary syndrome
2022, JHEP ReportsHepatopulmonary syndrome (HPS) is a pulmonary vascular complication of liver disease, which adversely affects prognosis. The disease is characterised by intrapulmonary vascular dilatations and shunts, resulting in impaired gas exchange. A complex interaction between the liver, the gut and the lungs, predominately impacting pulmonary endothelial cells, immune cells and respiratory epithelial cells, is responsible for the development of typical pulmonary alterations seen in HPS. Liver transplantation is the only therapeutic option and generally reverses HPS. Since the implementation of the model for end-stage liver disease (MELD) standard exception policy, outcomes in patients with HPS have been significantly better than they were in the pre-MELD era. This review summarises current knowledge and highlights what’s new regarding the diagnosis and management of HPS, and our understanding of pathogenesis based on experimental models and translational studies.
Hepatopulmonary Syndrome
2021, Encyclopedia of Respiratory Medicine, Second EditionHepatopulmonary syndrome (HPS) is a liver-induced pulmonary vascular abnormality that can cause severe arterial hypoxemia. Hypoxemia is due to ventilation-perfusion mismatching, diffusion-perfusion defects, and anatomic shunts. Circulating mediators emanating from the diseased liver have been implicated to cause intrapulmonary vascular dilatation, the hallmark of HPS. HPS has been associated with any type of liver disease or cause of portal hypertension. Aside from supplemental oxygen, medical therapies are of limited benefit in improving hypoxemia due to HPS. Remarkably, liver transplantation resolves the syndrome in most cases and is considered the treatment of choice.
Transjugular Intrahepatic Portosystemic Shunts: Advances and New Uses in Patients with Chronic Liver Disease
2020, Clinics in Liver DiseasePulmonary Complications of Portal Hypertension
2019, Clinics in Liver DiseaseEASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis
2018, Journal of HepatologyThe natural history of cirrhosis is characterised by an asymptomatic compensated phase followed by a decompensated phase, marked by the development of overt clinical signs, the most frequent of which are ascites, bleeding, encephalopathy, and jaundice. The following Clinical Practice Guidelines (CPGs) represent the first CPGs on the management of decompensated cirrhosis. In this context, the panel of experts, having emphasised the importance of initiating aetiologic treatment for any degree of hepatic disease at the earliest possible stage, extended its work to all the complications of cirrhosis, which had not been covered by the European Association for the Study of the Liver guidelines, namely: ascites, refractory ascites, hyponatremia, gastrointestinal bleeding, bacterial infections, acute kidney injury, hepatorenal syndrome, acute-on-chronic liver failure, relative adrenal failure, cirrhotic cardiomyopathy, hepatopulmonary syndrome, and porto-pulmonary hypertension. The panel of experts, produced these GPGs using evidence from PubMed and Cochrane database searches providing up to date guidance on the management of decompensated cirrhosis with the only purpose of improving clinical practice.