Animal Models Of Portal Hypertension Research Articles

Disrupted BMP-9 Signaling Impairs Pulmonary Vascular Integrity in Hepatopulmonary Syndrome.

Hepatopulmonary syndrome (HPS) is a severe complication of liver diseases characterized by abnormal dilatation of pulmonary vessels, resulting in impaired oxygenation. Recent research highlights the pivotal role of liver-produced bone morphogenetic protein (BMP)-9 in maintaining pulmonary vascular integrity. This study aimed to investigate the involvement of BMP-9 in human and experimental HPS. Circulating BMP-9 levels were measured in 63 healthy controls and 203 cirrhotic patients, with or without HPS. Two animal models of portal hypertension were employed: common bile duct ligation (CBDL) with cirrhosis and long-term partial portal vein ligation (PPVL) without cirrhosis. Additionally, the therapeutic effect of low-dose BMP activator FK506 was investigated, and the pulmonary vascular phenotype of BMP-9 knockout rats was analyzed. Patients with HPS related to compensated cirrhosis demonstrated lower levels of circulating BMP-9 compared to patients without HPS. Severe cirrhosis patients exhibited consistently low levels of BMP-9. In animal models, HPS characteristics, including intrapulmonary vascular dilations (IPVDs) and alveolo-arterial gradient enlargement, were observed. HPS development in both rat models correlated with reduced intrahepatic BMP-9 expression, decreased circulating BMP-9 level and activity, and impaired pulmonary BMP-9 endothelial pathway. Daily treatment with FK506 for 2-weeks restored BMP pathway in the lungs, alleviating IPVDs, and improving gas exchange impairment. Furthermore, BMP-9 knockout rats displayed a pulmonary HPS phenotype, supporting its role in disease progression. The study findings suggest that portal hypertension-induced loss of BMP-9 signaling contributes to HPS development.

Effects of Ultra-Low-Dose Aspirin in Thrombosis and Haemorrhage.

Aspirin is the oldest and possibly the most widely used pharmacologically active substance still used in allopathic medicine. Its effect on fever and inflammation has paved the way to its anti-thrombotic effect. Dilutions of aspirin have been tested for many years in the University of Bordeaux, in humans as well as in animal models. This article is a review of the totality of articles published by the Laboratory of Hematology of the Faculty of Pharmacy of the University of Bordeaux, reporting different doses and dilutions of aspirin, different kinds of inhibitors, transgenic mice and animal models of disease such as portal hypertension and cirrhosis. Homeopathic dilutions of aspirin, notably 15 cH, have shown a pro-thrombotic effect in humans and in in-vivo animal studies. Longitudinal studies in rats have also shown an initial anti-thrombotic effect followed by a pro-thrombotic effect of aspirin several days after a single high-dose administration. This pro-thrombotic effect seems to act by inhibiting the cyclooxygenase (COX)-2 pathway in studies performed with COX selective inhibitors and in knock-out mice without COX-1 or COX-2. This effect may explain the thrombo-embolic complications described after aspirin withdrawal for the purposes of surgery or after non-compliance with anti-platelet therapy, and it may be beneficial in normalising primary haemostasis and decreasing haemorrhage in animal models of portal hypertension and cirrhosis. Aspirin 15 cH acts through the inhibition of the COX-2 pathway producing a clear pro-thrombotic effect. Further studies should clarify if the pro-thrombotic effect of aspirin withdrawal and the effect of aspirin 15 cH are related, as secondary effects of the same drug. Clarifying this last outcome may be of great significance to public health.

Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats

Pathological angiogenesis represents a critical hallmark for chronic liver diseases. Understanding the mechanisms regulating angiogenesis is essential to develop new therapeutic strategies that specifically target pathological angiogenesis without affecting physiological angiogenesis. Here we investigated the contribution and therapeutic impact of the endogenous angioinhibitor vasohibin-1 in portal hypertension and cirrhosis. The spatiotemporal expression profiling of vasohibin-1 and its relationship with vascular endothelial growth factor (VEGF), angiogenesis, and fibrogenesis was determined through the analysis of human cirrhotic liver specimens, widely accepted in vivo animal models of portal hypertension and cirrhosis, and in vitro angiogenesis assays. Effects of vasohibin-1 overexpression by adenoviral-mediated gene transfer on angiogenesis, fibrogenesis, and portal hypertension-associated hemodynamic alterations were also studied in rats. We found that vasohibin-1 and VEGF are up-regulated, in mesentery and liver, in cirrhotic and precirrhotic portal hypertensive rats and cirrhosis patients. Our results are consistent with vasohibin-1/VEGF cascades being spatially and temporally coordinated through a negative-feedback loop driving pathological angiogenesis. Paradoxically, further overexpression of vasohibin-1 by adenoviral gene transfer exerts multifold beneficial effects in portal hypertension and cirrhosis: reduction of pathologic angiogenesis, attenuation of liver fibrogenesis partly mediated through inhibition of hepatic stellate cell activation, and significant decreases in portocollateralization, splanchnic blood flow, portohepatic resistance, and portal pressure. The explanation for this apparent contradiction is that, unlike endogenous vasohibin-1, the ectopic overexpression is not regulated by VEGF and therefore disrupts the negative-feedback loop, thus generating constant, but lower levels of VEGF synthesis sufficient to maintain vascular homeostasis but not pathological angiogenesis. Our study provides evidence that vasohibin-1 regulates portal hypertension-associated pathological angiogenesis and highlights that increasing vasohibin-1 might be a promising novel therapeutic strategy for portal hypertension and cirrhosis.

Hemodynamic changes on animal models of portal hypertension after spleen and liver shunt

Objective To observe portal hemodynamic changes in miniature pigs with liver cirrhosis and portal hypertension after distal splenic vein-hepatic artery shunt (spleen and liver shunt).Methods Fifteen pre-built miniature pigs with liver cirrhosis and portal hypertension received spleen and liver shunt.The portal vein district outside the liver was divided into two separated and no-connect areas:stomach-spleen area and mesenteric up and down area postoperatively.After feeding for 30 days,pigs were subjected to re-open operation to get relevant data.Results (1) After the spleen and liver shunt,portal vein pressure was (23.49 ±1.10) cm H2O (1 cm H2O =0.098 kPa),and (21.53 ±1.26) cm H2O after 30 days (P ＞0.05) ; splenic vein pressure was (35.45 ±2.88) cm H2O,and (23.09 ± 1.36) cm H2O after 30 days (P ＜ 0.05) ; portal vein-splenic vein pressure difference was (17.90 ± 3.31) cm H2O,and (9.55 ± 1.32) cm H2O after 30 days (P ＜0.05) ; (2) Blood from stomach-spleen area flowed into the liver by the spleen and liver shunt,and the liver stained well after methylene blue was injected into the splenic vein.Conclusion Extrahepatic portal vein blood flow channel changed after the spleen and liver shunt,the overall portal hemodynamics was not affected,and a new balanced mechanism was established to maintain hemodynamic stability.The new balancing mechanism is maintained by the pressure difference as the driving force. Key words: Liver cirrhosis ; Portal hypertension; Model, animal; Spleen and liver shunt; Portal hemodynamic

Portal hypertension correlates with splenic stiffness as measured with MR elastography

To investigate the correlation between MR elastography (MRE) assessed spleen stiffness and direct portal vein pressure gradient (D-HVPG) measurements in a large animal model of portal hypertension. Cholestatic liver disease was established in adult canines by common bile duct ligation. A spin echo based echo planar imaging (EPI) MRE sequence was used to acquire three-dimensional/three axis (3D/3-axis) abdominal MRE data at baseline, 4 weeks, and 8 weeks. Liver biopsies, blood samples, and D-HVPG measurements were obtained simultaneously. Animals developed portal hypertension (D-HVPG: 11.0 ± 5.1 mmHg) with only F1 fibrosis after 4 weeks. F3 fibrosis was confirmed after 8 weeks despite no further rise in portal hypertension (D-HVPG: 11.3 ± 3.2 mmHg). Mean stiffnesses of the spleen increased over two-fold from baseline (1.72 ± 0.33 kPa) to 4 weeks (3.54 ± 0.31 kPa), and stabilized at 8 weeks (3.38 ± 0.06 kPa) in a pattern consistent with changes in portal pressure. A positive correlation was observed between spleen stiffness and D-HVPG (r(2) = 0.86; P < 0.01). These findings indicate a temporal relationship between portal hypertension and the development of liver fibrosis in a large animal model of cholestatic liver disease. The observed direct correlation between spleen stiffness and D-HVPG suggest a noninvasive MRE approach to diagnose and screen for portal hypertension.

Inhibition of Nitric Oxide Synthase in Hyperdynamic Circulation of Rats with Early or Late Cirrhosis Secondary to Common Bile Duct Ligation

Preventing internal hemorrhage extends the lifespan of rats with chronic bile duct ligation (CBDL), a common animal model of portal hypertension. We investigated hemodynamics during the early and late stages of cirrhosis caused by CBDL. We also evaluated the hemodynamic influence of NO, which is the chief vasodilator in hyperdynamic syndrome, by administration of an NO synthase inhibitor (N(G)-nitro-L-arginine methyl ester: L-NAME; 10 mg/kg). ANIMALS/METHODS: In 24 Sprague-Dawley rats (9 sham rats and 15 CBDL rats), hemodynamics were assessed under conscious and unrestrained conditions 4 and 8 weeks after surgery. Before and 30 minutes after L-NAME administration, the cardiac index (CI) and regional blood flow were measured with the reference sample method using (141)Ce- and (113)Sn-microspheres (15 µm in diameter). A hyperdynamic systemic circulation and splanchnic hyperemia were observed after CBDL, and these changes increased with the progression of cirrhosis. L-NAME significantly diminished the hyperdynamic circulation and also reduced splanchnic hyperemia. In 4-week CBDL rats, a low hemoglobin concentration made an important contribution to the hyperdynamic circulation, and the portal collateral system collapsed when inflow to the portal territory was reduced by L-NAME treatment. In 8-week CBDL rats, systemic hemodynamics were closely linked to both the splanchnic circulation and the renal circulation before and after L-NAME administration, apart from hepatic artery blood flow. The distinctive hemodynamic changes of portal hypertension were found in 8-week CBDL rats. Thus, 8-week CBDL rats may be a better animal model of human portal hypertension than 4-week CBDL rats.

A canine portal hypertension model induced by intra‐portal administration of Sephadex microsphere

Big animal models of portal hypertension are important for the research into this disease. The aim of this study was to establish a canine portal hypertension model by intra-portal administration of microspheres. Sixteen mongrel dogs were assigned to control group and experimental group randomly. The catheterization of portal vein was performed by laparotomy and the outer end of the catheter was fixed subcutaneously in the abdominal wall. The dogs of the experimental group were given intra-portal injections of microspheres at a five-day interval, six times in total. Portal hemodynamics, blood cell counting, liver and renal function test, portography, gastroscopy, liver, spleen and lung histological examination were taken to evaluate the model. 1, 2, 3 and 4 months after initial injection of microspheres, portal venous pressure rose from baseline 8.7 +/- 0.7 mmHg to 24.3 +/- 1.6, 20.6 +/- 2.1, 19.0 +/- 1.8 and 17.7 +/- 2.0 mmHg, respectively (P < 0.01). The diameter of portal vein increased from 7.6 +/- 0.3 to 8.6 +/- 0.3 mm, calculated portal resistance increased from 0.46 +/- 0.06 to 1.06 +/- 0.20 (mmHg/mL/min/kg body weight); velocity of portal blood flow decreased from 35.1 +/- 1.7 to 26.1 +/- 2.4 cm/s (P < 0.01, respectively). The animals of experimental group developed marked splenomegaly and profuse portosystemic collateral circulations with normal liver and renal function. Repeated intra-portal administration of microspheres can induce stable and reproducible chronic portal hypertension in dogs with normal liver and renal functions. This model can meet multiple demands of both basic and clinical research of portal hypertension.

Circulating vascular endothelial growth factor and nitric oxide in patients with liver cirrhosis: A possible association with liver function impairment

Hemodynamic disorders of liver cirrhosis complicated with portal hypertension are associated with an increased angiogenesis in animal model of portal hypertension and cirrhosis which were linked to increased expression of vascular endothelial growth factor (VEGF) and nitric oxide (NO). The aim of study was to evaluate the serum concentration of VEGF and total nitric oxide (NO) in liver cirrhosis and the possible association with the degree of liver insufficiency. VEGF and NO were measured in serum of 64 patients with liver cirrhosis by ELISA and spectrophotometry respectively. The significant increase of serum VEGF was observed in liver cirrhosis compared to healthy individuals as well as serum NO (106.1 ± 66.7 vs. 41.5 ± 6 pg/mL, P < 0.05; 113.5 ± 65.8 vs. 20.8 ± 3.8 μmol/l, P< 0.001, respectively). Serum VEGF and NO showed significant associations with biochemical indices of liver function and with Child-pugh score where they were increased respectively to the degree of liver insufficiency. A significant association of raised serum NO in early stage of portal hypertension reflect its benefit in early expect of portal hypertension but, high serum VEGF in late stage may reflect its prognostic value in liver cirrhosis.

Pharmacological effects are model specific in animal models of portal hypertension

Pharmacological effects are model specific in animal models of portal hypertension

Circulating vascular endothelial growth factor and its soluble receptors in patients with liver cirrhosis: Possible association with hepatic function impairment

Recent studies provided in vivo evidences of an increased angiogenesis in animal model of portal hypertension and cirrhosis which was linked to increased expression of vascular endothelial growth factor. The aim of study was to evaluate the plasma concentration of VEGF and its receptors in liver cirrhosis and the possible association with the degree of liver insufficiency. Methods. Vascular endothelial growth factor (VEGF) and its soluble receptors: sVEGF-R1, sVEGF-R2 were measured in plasma of 78 patients with liver cirrhosis by ELISA. Results. The significant increase of plasma VEGF and sVEGF-R1 was observed in liver cirrhosis compared to healthy individuals (153.1 ± 51.9 vs. 46.8 ± 4.1 pg/mL, P < 0.05; 279.8 ± 34.3 vs. 105.1 ± 5.9 pg/mL, P < 0.001, respectively). Plasma VEGF and foremost sVEGF R1 showed significant associations with biochemical indices of liver function. Among clinical parameters, only ascites revealed significant association with plasma VEGR and sVEGF-R1. VEGF and sVEGF-R1 were increased respectively to the degree of liver insufficiency. It was demonstrated through a significant positive correlation with Child-Pugh score and MELD classification. In conclusion, our study suggests that serum VEGF and VEGF-R1 may reflect the hepatic function impairment in liver cirrhosis and seems to be associated with portal hypertension symptoms.

The Effect of Vasopressin and Related Compounds at V1a and V2 Receptors in Animal Models Relevant to Human Disease*

Vasopressin, a neurohypophyseal peptide hormone, is the endogenous agonist at V1a, V1b and V2 receptors. The most important physiological function of vasopressin is the maintenance of water homeostasis through interaction with V2 receptors in the kidney. Vasopressin and related compounds are used in various clinical settings such as acute variceal bleeding associated with portal hypertension, septic shock, diabetes insipidus and coagulation disorders. The effect in the former two indications relates to the V1a receptor, and in the two latter indications the effect relates to the V2 receptor. Vasopressin and related compounds have demonstrated activity in animal models of portal hypertension, sepsis and septic shock, diabetes insipidus and coagulation disorders. The use of the compounds in animal models is reviewed. Generally, the effect of vasopressin and related compounds in animal models reflect the activity in the clinical setting, but in some cases important species differences exist.

Animal models of portal hypertension

Animal models have allowed detailed study of hemodynamic alterations typical of portal hypertension and the molecular mechanisms involved in abnormalities in splanchnic and systemic circulation associated with this syndrome. Models of prehepatic portal hypertension can be used to study alterations in the splanchnic circulation and the pathophysiology of the hyperdynamic circulation. Models of cirrhosis allow study of the alterations in intrahepatic microcirculation that lead to increased resistance to portal flow. This review summarizes the currently available literature on animal models of portal hypertension and analyzes their relative utility. The criteria for choosing a particular model, depending on the specific objectives of the study, are also discussed.

Modelos animales en el estudio de la hipertensión portal

Animal models allow detailed study of the hemodynamic alterations in portal hypertension syndrome and of the molecular mechanisms involved in the abnormalities in splenic and systemic circulation associated with this syndrome. Models of prehepatic portal hypertension can be used to study alterations in the splenic circulation and the physiopathology of hyperdynamic circulation. Moreover, models of cirrhosis allow the alterations in intrahepatic microcirculation that lead to increased resistance to portal flow to be studied. The present review summarizes currently available animal models of portal hypertension and analyzes their relative utility in investigating the distinct disorders associated with this entity. The criteria for the choice of a particular model, depending on the specific objectives of the study, are also discussed.

Portal hypertension enhances endotoxin-induced intercellular adhesion molecule 1 up-regulation in the rat

BACKGROUND & AIMS: Liver disease or portosystemic shunting enhances th e sensitivity to endotoxin. The aim of this study was to investigate whether intercellular adhesion molecule 1 (ICAM-1) expression in response to endotoxin may be dysregulated in an animal model of portal hypertension. METHODS: Portal hypertension was induced by partial portal vein ligation. Sham-operated animals served as controls. ICAM-1 expression was measured using radiolabeled antibodies under baseline conditions or 5 hours after treatment with either endotoxin or recombinant tumor necrosis factor (TNF). Immunoreactive plasma TNF was also measured. RESULTS: Under baseline conditions, ICAM-1 expression in all organs studied was similar in portal-hypertensive and sham-operated rats. ICAM-1 up-regulation after a high dose of endotoxin (5 mg/kg) was similar in both groups of animals. However, portal-hypertensive animals showed a significantly higher ICAM-1 expression in response to low doses of endotoxin (0.1-10 microgram/kg). The response to a low (but not a high) dose of recombinant TNF was also significantly enhanced in portal-hypertensive animals. In addition, portal-hypertensive rats had higher plasma TNF levels after treatment with endotoxin or recombinant TNF. CONCLUSIONS: Portal hypertension induces an exaggerated ICAM-1 up- regulation in response to endotoxin, which is related to an increased production and decreased clearance of the cytokine. (Gastroenterology 1996 Mar;110(3):866-74)

Animal model of portal hypertension with observations regarding the relationship between portal flow and pressure.

The feasibility of producing acute portal hypertension in a porcine model was evaluated to test the relationship between portosystemic shunt flow and portal pressure. Percutaneous transhepatic cannulation of the portal vein and cutdown of a systemic vein was accomplished in anesthetized pigs. The portal system was subsequently embolized with polyvinyl alcohol (Ivalon) particles. Portosystemic shunting was performed with the assistance of a centrifugal pump. Portal hypertension could be routinely produced, and portosystemic shunting was successfully studied in three of four animals. Linear changes in shunt flow led to exponential pressure changes. This animal model provides a representation of acute portal hypertension that provides useful data regarding the compliance of the portal system and illustrates the pressure/flow relationship.

Current concepts in the pathophysiology and treatment of portal hypertension and variceal hemorrhage

Recent studies have demonstrated that increased resistance to portal inflow is not solely responsible for the development of portal hypertension. Increased splanchnic flow has been attributed to a combination of factors, including elevated circulating levels of vasodilators and diminished sensitivity of the splanchnic vasculature to endogenous vasoconstrictors. In selected animal models of portal hypertension, increased splanchnic flow accounts for approximately 40% of the observed elevations in total portal venous pressure. Improved understanding of the pathophysiologic factors responsible for the development of portal hypertension has led to pharmacologic efforts to decrease portal pressure. Current limitations include lack of drug selectivity and specificity and inability to predict and monitor patient responses. Primary treatment options include selective portosystemic shunts, endoscopic sclerotherapy (ES), and orthotopic liver transplantation. ES is more effective in preventing recurrent variceal hemorrhage than medical treatment but is less effective than shunt surgery. In selected studies, ES better maintains hepatic function and may prolong survival compared to primary shunt surgery. ES failures occur in nearly 33% of patients, but "salvage shunts" in these patients appear to be reasonably safe and quite effective in preventing recurrent hemorrhage. Selective shunts are favored because they appear to confer a better quality of life (but not improved longevity) than conventional shunts. Liver transplantation is preferred for patients with end-stage liver disease in whom the predicted mortality of conventional surgery outweighs the survival benefit.

Animal models of portal hypertension: By S.K. Sarin and N.C. Nayak. 141 pp., $16.95. Kunj Publishing House, New Delhi, India, 1988

Animal models of portal hypertension: By S.K. Sarin and N.C. Nayak. 141 pp., $16.95. Kunj Publishing House, New Delhi, India, 1988

Animal models of portal hypertension: By S.K. Sarin and N.C. Nayak. 141 pp., $16.95. Kunj Publishing House, New Delhi, India, 1988

Animal models of portal hypertension: By S.K. Sarin and N.C. Nayak. 141 pp., $16.95. Kunj Publishing House, New Delhi, India, 1988